99% Human and 1%Animal?

Patentable
Subject Matter and Creating Organs via
Interspecies Blastocyst Complementation
Jerry I-H Hsiao*

INTRODUCTION

A shortage of human organs creates a long waitlist for vital

transplants. According to the U.S. Government Information on Organ
Donation and Transplantation, there are currently over 110,000 patients on
the waiting list for organ transplants.1 Every day, about twenty-two people
needing various organs die while they wait.2 Thousands of patients
continue to die while awaiting organ transplantation each year.3 While
efforts have been made to generate functional mature cells from induced
Pluripotent Stem Cells (hereinafter “iPSC”) targeting diseases that are
potentially amenable to treatment by cell transplantation, other diseases
such as heart, kidney, liver, and lung failure require whole organ
transplant.4
The growing shortage of available organs is very difficult to overcome.
Traditionally, two solutions are being considered: (1) extending the life
span of patients awaiting transplants and (2) developing new, alternative
methods for obtaining transplantable organs.5 The current practice of organ

* Dr. Jerry I-H Hsiao is Assistant Professor of Law at the Faculty of Law, University of
Macau. Prior to his current appointment, he was Lecturer in Law at the Liverpool Law School,
University of Liverpool (UK) as well as affiliated Lecturer in Law at School of Law, University
of Reading (UK). Dr. Hsiao obtained his PhD from the University of London (UK) and LLM
from Newcastle University (UK). His research interests include: patent and copyright policy,
innovation policy, health law and policy as well as cross-strait relationships between China
and Taiwan. He has published more than 30 articles, book chapters as well as conference
proceedings relating to his fields of research.
1 Health Resources & Services Administration, Organ Donation Statistics,
https://perma.cc/7ZQC-MHEL (last visited Oct. 29, 2019).
2 Kelly Servick, CRISPR Slices Virus Genes out of Pigs, but Will It Make Organ Transplants to

Humans Safer?, SCIENCE (Aug. 10, 2017, 2:00 PM), https://perma.cc/6FY9-YMW3.

3 Raffaela Girlanda, Deceased Organ Donation for Transplantation: Challenges and
Opportunities, 6(3) WORLD J. TRANSPLANTATION 451–59 (2016).
4 Jun Wu et al., Stem Cells and Interspecies Chimeras, 540 NATURE 51-59 (2016).
5 Magdalena Hryhorowicz et al., Genetically Modified Pigs as Organ Donors for
Xenotransplantation, 59 MOLECULAR BIOTECHNOLOGY 435, 435 (Jul. 11, 2017),
https://perma.cc/FMK7-GKTZ.

101
102 New England Law Review [Vol. 53

transplantation involves two distinct types:6 autotransplantation and

allotransplantation. Autotransplantation is a process through which
material is harvested and subsequently transplanted from one part of an
individual’s body to another. Allotransplantation occurs where material is
harvested from one individual and subsequently transplanted to another
individual intra-species. The challenges associated with allogenic
transplantation include:7 (1) donor-recipient blood type compatibility; (2)
donor-recipient physical compatibility (e.g. organ size, life span); (3) the
transmission of pathogens (e.g. human immunodeficiency virus, as well as
hepatitis B and C viruses); (4) the use of immunosuppressive
pharmaceutical to circumvent transplant immunorejection; and (5) chronic
donor organ shortage.8
A particular issue over organ transplantation centers on rejection.9
There are two main types of rejection: (1) “Host vs Graft”; and (2) “Graft vs
Host”. “Host vs Graft” rejection is the common type of rejection and starts
on a biomolecular level which eventually leads to the host’s body rejecting
the transplant. Rejection occurs when a recipient’s T-cells recognize a
foreign variation of proteins on the surface of transplant’s cells, located in a
region known as the major histocompatibility complex. 10 “Graft vs Host”
rejection occurs in the reverse where the donor’s cells reject the body it has
been transplanted in. “Graft vs Host” is more commonly seen in bone
marrow transplants as opposed to whole organ transplants.
Although efforts to enlarge the human donor pool have improved
organ availability, even a massive expansion in organ donation would not
ensure that a compatible organ would be available when and where
necessary for a patient in need. Therefore alternatives besides expanded
human organ donations are required.11 The ultimate goal of regenerative
medicine is the transplantation of target organ generated by the patient’s
own cell which could be achieved through techniques such as tissue
engineering,12 organ therapeutic cloning,13 and, 3D Bioprinting.14 Recently,

6 Gregory R. Hagen & Sébastien A. Gittens, Patenting Part-Human Chimeras, Transgenics and

Stem Cells for Transplantation in the United States, Canada, and Europe, 14 RICH. J.L. & TECH. 1, 7
(2008), https://perma.cc/AKY7-7W93.
7 See id.
8 Lechler et al., Organ Transplantation-How Much of the Promise Has Been Realized? 11
NATURE MED. 605 (2005).
9 Joshua R. Gershlak, Engineering New Tissues and Organs: How We Can Eliminate the Massive

Organ Shortage in the United States, 14 J. HEALTH & BIOMEDICAL L. 83, 86 (2018).
10 AMITAVA DASGUPTA & AMER WAHED, CLINICAL CHEMISTRY, IMMUNOLOGY, AND

LABORATORY QUALITY CONTROL: A COMPREHENSIVE REVIEW FOR BOARD PREPARATION,

CERTIFICATION, AND CLINICAL PRACTICE, 427–47 (2014).
11 SEAN STEVENS, GENETIC ENGINEERING: GENOME ENGINEERING FOR
XENOTRANSPLANTATION (Farrukh Jamal ed. 2019), available at https://perma.cc/8VLR-8Y4W.
12 See Gershlak, supra note 9, at 89–92.
2019] 99% Human and 1% Animal? 103

a technique of organ generation using pluripotent stem cells and blastocyst

complementation in xenotransplantation has also raised interest in solving
the current organ shortage.
This article aims to discuss whether organs produced via interspecies
blastocyst complementation (IBC) are patentable subject matter under both
35 U.S.C. § 101 and Leahy-Smith America Invents Act (AIA) § 33 (a).
Section 2 provides the scientific background of xenotransplantation and
interspecies blastocyst complementation. Section 3 examines the patent
eligibility jurisprudence of nature-based products. Section 4 examines
current patents on xenotransplantation while § 5 examines current patent
applications of organs generated via interspecies blastocyst
complementation. Section 6 will provide policy recommendations for
patenting organs via interspecies blastocyst complementation.

I. Creating Artificial Organs for Transplantation to Humans

Xenotransplantation

Xenotransplantation, or the transplantation, implantation, or infusion

into a human recipient of cells, tissues, or organs from a non- human
animal source,15 has the potential to overcome critical need for organs to
treat patients. The concept of xenotransplantation is relatively old, when
Emerich Ullman first transplanted a pig kidney into the arm of a woman in
1902.16 The results, however, were not promising and are often rejected by
the recipient’s immune system.17 In the past, this issue is alleviated through
immunosuppressive regimen, but this approach is in itself problematic as it
might leave patients susceptible to infections and possibly cancer. 18
Nowadays, the issue of immune rejection ceases to be a grave concern due
to the advances in gene-editing technologies. Researchers can develop
genetically engineered animals with organs closer to what many believe
human immune system could accept.19 The method is to specifically target
what is causing the rejection and remove that gene which will also reduce

13 See Chester J. Koh & Anthony Atala, Therapeutic Cloning Applications for Organ
Transplantation, 12 TRANSPLANT IMMUNOLOGY 193, 193–94 (2004).
14 See Jerry I-H Hsiao, Patent Eligibility of 3D Bioprinted Organs in Taiwan, 28 ALB. L.J. SCI. &

TECH. 1, 2 (2018).
15 Hagen, supra note 6, at 1–2.

16 Luis H. Toledo-Pereyra & F. Lopez-Neblina, Xenotransplantation: A View to the Past and an

Unrealized Promise to the Future, 1 EXPERIMENTAL CLINICAL TRANSPLANT 1, 1 (2003).

17 See Emily Waltz, When Pig Organs Will Fly, 35 NATURE BIOTECHNOLOGY 1133, 1137

(2017).
18 See generally Deborah Ku, The Patentability of the CRISPR-CAS9 Genome Editing Tool, 16
CHI.-KENT J. INTELL. PROP. 408, 416-17 (2017) (defining CRISPR as a genome editing tool,
which is cheaper, simpler and more efficient than other currently available gene editing tools).
19 Waltz, supra note 17, at 1133.
104 New England Law Review [Vol. 53

the need for immune suppressive drugs. 20 Furthermore, researchers are

also adding human transgene that produces protein into pigs to enable pig
organs to function once transplanted into humans. 21
Currently, pigs make attractive animals to bear human organs because
the size of their organs are similar to the size of human organs. Also, their
metabolism is close to the human metabolism and lastly, there is important
corpus of knowledge in humans within the context of xenotransplantation
trials.22 Maryland-based United Therapeutics founder Martine Rothblatt
aims to use technologies to create an unlimited supply of transplantable
organs using genetically modified pigs. The goal is to produce organs with
“99 percent pig genome, with a little bit of human genome” to make them
tolerable to humans.23 Eventually she aims to take pig hearts, strip them of
everything that makes them porcine, and replace them with human cells,
creating something that makes the organ have the “scaffold of a pig’s
lungs, but all the cells will be human.”24
One issue on transplanting organs from pigs into human is the concern
over porcine endogenous retroviruses (PERVs), “strands of potentially
pathogenic DNA in the animals’ genome,” which might infect humans and
eventually cause diseases.25 PERVs are very difficult to eliminate, as they
are encoded in multiple locations in pig genome. 26 In 2015, a group of
scientists at Harvard demonstrated that they have successfully used
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to
eliminate all 62 PERVs in porcine cells.27 However, PERVs are not the only
obstacle in transplant-ready pig organs; researchers will also need to use
CRIPSR to knock out pig genes that provoke human immune system and
insert others to prevent toxic interactions with human blood.28

II. Interspecies Blastocyst Complementation

Xenotransplantation, nevertheless, still persists with problems such as

20 Waltz, supra note 17, at 1133.

21 Waltz, supra note 17, at 1134.
22 Rodolphe Bourret et al., Human-Animal Chimeras: Ethical Issues about Farming Chimeric

Animals Bearing Human Organs, 7 STEM CELL RES. THER. 87 (2016).

23 Jason Koebler, Martine Rothblatt Wants to Grow Human Organs in Pigs at This Farm,

MOTHERBOARD (June 24, 2015), https://perma.cc/48DT-LX2K.

24 Id.
25 Caroline Perry, Pig Organs for Human Patients: A Challenge Fit for CRISPR, WYSS INST.
(May 30, 2018), https://perma.cc/7GMR-JK3Q.
26 See Jun-Heon Lee et al., Characterizing and Mapping Porcine Endogenous Retroviruses in

Westran Pigs, 76 J. VIROLOGY 5548 (2002).

27 Luhan Yang et al., Genome-Wide Inactivation of Porcine Endogenous Retroviruses (PERVs),

350 SCIENCE 1101, 1101 (2015).

28 Servick, supra note 2.
2019] 99% Human and 1% Animal? 105

the degree of engineering required and the fact that heavy

immunosuppression might still be needed in some patients. 29 Some
researchers have adopted IBC to create human/nonhuman chimera as
incubators for human organs.
Recently introduced technologies, especially interspecies chimera 30
generated with human pluripotent stem cells (PSC) or iPSC, show the
possibility of producing human organs in genetically-modified chimera
pigs.31 IBC composes several stages: (1) using CRISPR to knock out a gene
for creating an organ (e.g. lung) to create a niche in the animal embryo; (2)
reprogramming human somatic cells to generate conventional human
iPSC; (3) converting conventional human iPSC into a chimera-competent
state; (4) human xenogenic PSC are then introduced into the host animal
by blastocyst injection; and (5) the resulting chimeric embryo 32 is
transferred into the foster animal mother.33 Human iPSC-derived organs
would be genetically identical to their intended patients and recipients,
thus avoiding immune rejection or complications of immunosuppression
regimens.34
In order to develop an IBC platform, it is necessary to create genetically
modified animal host and human chimera-competent PS cells.35 However,
studies have shown that, currently, it is very difficult for conventional
human PS cells to correspond to a chimera-competent cellular state.36 While
CRISPR will enable the generation of appropriately customized animal
hosts, significant obstacles remain; for example, interspecies barrier makes

29 See Waltz, supra note 17, at 1136.

30 See Waltz, supra note 17, at 1135–36 (explaining that a chimera is composed of some cells
from one species, which contain genetic material derived entirely from that species, and some
cells from another species containing only genetic material from that species and that humans
have been creating chimera prior to the advent of IBC by using pig and cow heart valves to
replace faulty human heart valves).
31 Wanyou Feng et al., The Potential of the Combination of CRISPR/Cas9 and Pluripotent Stem

Cells to Provide Human Organs from Chimaeric Pigs, 16 INT’L J. MOLECULAR SCI. 6545, 6546
(2015).
32 See Waltz supra note 17 (explaining that a chimera is composed of some cells from one

species, which contain genetic material derived entirely from that species, and some cells from
another species containing only genetic material from that species and thus, the cells in a
chimeric animal always remain segregated by species, and no cell contains genetic material
from both species).
33 See Alejandro De Los Angeles et al., Generating Human Organs via Interspecies Chimera

Formation: Advances and Barriers, 91 YALE J. BIOLOGY MED. 333, 335 (2018),
https://perma.cc/AJH5-XBGV.
34See Asuisa Marizane et al., MHC Matching Improves Engrafting of iPSC Derived Neurons in
Non-Human Primates, 8 NATURE COMMUNICATIONS 385, 385 (2017), https://perma.cc/R2DC-
MSG2.
35 De Los Angeles, supra note 33, at 335.
36 De Los Angeles, supra note 33, at 336.
106 New England Law Review [Vol. 53

getting human stem cells to proliferate in an animal embryo akin to trying

to grow rice in dry sand.37 In January 2017, Juan Carlos Ippisua Belmonte
and his team at Salk institute created the first human-pig chimera using
IBC. However, the presence of human iPSC is very low–one human cell for
every 100,000 pig cells.38

III. Evolution of Patent Eligibility Inquiry for Nature-Based

Products

The U.S. Constitution grants Congress the power “to promote the
Progress of Science and useful Arts, by securing for limited Times to
Authors and Inventors the exclusive Right to their respective Writings and
Discoveries.”39 The statutory requirements for patent eligibility are laid out
in U.S.C § 101 and are supplemented by the Manual of Patent Examining
Procedure (MPEP).40 Furthermore, § 33 of AIA states that “notwithstanding
any other provision of law, no patent may issue on a claim directed to or
encompassing a human organism.”41 Hence, one who wishes to seek patent
protection for artificial organ inventions would have to satisfy the
requirements set forth in the cases regarding nature-based products and to
avoid falling into the meaning of “human organism.”
Two specific issues will arise for organs generated via IBC. First,
despite the complicated process in creating the artificial organ, the organ
produced is meant for organ transplantation to the patient in need and to
replace the patient’s original organ. While the artificial organ is the
combination of two different species, it is created by using naturally
occurring raw materials. Will this be seen as trying to mimic the nature and
hence barred under the Product of Nature doctrine?42 Second, even if the
product would be different from what currently exists in nature, since the
artificial organ produced via IBC incorporates human iPSC and creates a
human/nonhuman chimera, would this be barred under AIA § 33(a) as
encompassing or being directed to human?
When a law of nature or natural phenomenon is claimed as a physical
product, the courts have often referred to the patent eligibility exception as

37 See Waltz, supra note 17, at 1136.

38 See Jun Wu et al., Interspecies Chimerism with Mammalian Pluripotent Stem Cells, 168 CELL
473, 474 (2017).
39 U.S. CONST. art. I, § 8, cl. 8.

40 MPEP §§ 2104–06 (9th ed. Rev. Jan. 2018).

41 Leahy-Smith America Invents Act, Pub. L. No. 112–29, 125 Stat. 284 (2011) (codified as

amended in scattered sections of 35 U.S.C.).

42 See generally MPEP § 2106.4(c) (examining that the Product of Nature Doctrine is an

exception to inventions that are otherwise patentable and was established as a limitation to
the broad language of section 101 which provides that “laws of nature, physical phenomenon,
and abstract ideas” are not patent eligible).
2019] 99% Human and 1% Animal? 107

a Product of Nature under 35 U.S.C. § 101.43 One of the reason for

disallowing the granting of patents to subject matter covering product of
nature is to prevent tying up the use of naturally occurring things. 44 The
Supreme Court has addressed patent eligibility several times over the past
decades, illustrated in the following cases.

IV. Diamond v. Chakrabarty (Genetically Engineered

Microorganisms)

In Diamond v. Chakrabarty, the Court held that genetically-modified

living microorganisms were not products of nature and thus patent
eligible.45 The Chakrabarty patent claimed a man-made bacterium,
genetically engineered and not existing in nature, was capable of breaking
down multiple components of crude oil.46 The Court ruled that the claim
was a non-naturally-occurring manufacture or composition of matter, and
the bacterium was deemed a product of human ingenuity that had “a
distinctive name, character, and use.”47 By finding the bacteria had
characteristics “markedly different . . . from any found in nature . . .” and
was patent eligible, the Court acknowledged that pioneering work by
scientists in the U.S. should be promoted and protected by the patent
system.48

V. Ex Parte Allen (Non-Naturally Occurring Oyster)

In Ex parte Allen, the patentee sought to patent polyploid oysters on the

basis that their polyploidy was induced by the application of pressure on
oyster zygotes by the patentee.49 The Board noted that under Chakrabarty’s
holding that § 101 included man-made life forms; “the issue . . . in
determining whether the claimed subject matter is patentable . . . is simply
whether that subject matter was made by man.”50 Thus, the Board
concluded that the oysters were non-naturally occurring animals made by
man was patentable subject matter.
Subsequently, there are three Supreme Court cases which helped to

43 See, e.g., Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116–17

(2013); Univ. of Utah Research Found. v. Ambry Genetics, Co., 774 F.3d 755, 758–59 (Fed. Cir.
2014).
44 Myriad Genetics, Inc., 133 S. Ct. at 2116–17.
45 See Diamond v. Chakrabarty, 447 U.S. 303 (1980).
46 Id. at 303.

47 Id. at 309–10.

48 Kevin Madigan & Adam Mossoff, Turning Gold into Lead: How Patent Eligibility Doctrine is

Undermining U.S. Leadership in Innovation, GEO. MASON L. REV. 939, 943 (2017).
49 Ex parte Allen, 2 U.S.P.Q.2d 1425, 1426 (Bd.Pat.App. & Interf. 1987), aff’d, 846 F.2d 77

(Fed. Cir. 1988).

50 Id.
108 New England Law Review [Vol. 53

form the patent eligibility test today. Mayo, Myriad, and Alice are not cases
on the patent eligibility of living organisms but rather cases featuring laws
of nature, products of nature, and abstract ideas respectively. By
incorporating Chakrabarty and Myriad’s markedly different tests, Mayo and
Alice formed a two-part test for examining patent eligibility for inventions
directed at nature-based products.

A. Mayo v. Prometheus (Laws of Nature)

In Mayo v. Prometheus,51 the claims at issue concerned a method for

administering a thiopurine drug by measuring the concentration of certain
metabolites in a patient’s blood and then adjusting the drug dosage to hone
in on an optimal level of metabolites.52 This led to the Mayo Court’s two-
step test. First, determine if the invention is directed at one of the judicial
categories of ineligible subject matter. If so, second, ask if the patent claims
add enough to their statement of the correlations of laws of nature to allow
the processes they describe to qualify as patent-eligible processes that
apply natural laws.53 The Mayo Court considers the claimed methods are
simply instructions which add nothing specific to the laws of nature other
than what is routine, conventional activity.

B. Ass’n for Molecular Pathology v. Myriad Genetics (Product of

Nature)

In Ass’n for Molecular Pathology v. Myriad Genetics, Myriad identified the

location and sequence of two human genes (BRCA1 and BRCA2), and was
granted patents claiming the DNA segments of these two genes.54 One was
directed at isolated, naturally-occurring DNA,55 and the other was directed
at complementary DNA (cDNA) synthesized from naturally-occurring
DNA.56 The Court held that isolated, naturally occurring DNA segments
were not patent eligible.57 In contrast, the claims for the cDNA were found
to be patent eligible because the cDNA lacked some sequence segments
normally found in natural DNA.58 The Myriad Court reiterated that
according to Chakrabarty, central to patent eligibility is whether an
invention is new with “markedly different characteristics from any found

51 See Mayo Collaborative Servs. v. Prometheus Labs Inc., 566 U.S. 132 (2012).
52 Id. at 1291. (directing doctors to: (1) measure the current level of the relevant metabolite,
(2) use particular (unpatentable) laws of nature to calculate the current toxicity/inefficacy
limits, and (3) reconsider the drug dosage in light of the law).
53 Id. at 1297.
54 Molecular Pathology v. Myriad Genetics, Inc., 589 U.S. 576, 579–80 (2013).
55 Id. at 579.
56 Id. at 579–80.
57 Id. at 580.
58 Id.
2019] 99% Human and 1% Animal? 109

in nature.” Myriad failed to achieve this because it did not create or alter
either the genetic information encoded in the BRCA1 or BRCA2 genes or
the genetic structure of the DNA.59

C. The Modern Approach on §101 Analysis: Alice (Abstract Ideas)

Based largely from Mayo, in Alice Corp. Pty. v. CLS Bank International,60
the Supreme Court articulated a two-part test in deciding patent eligibility.
The first step of the Alice framework is to determine “whether the claims at
issue are directed to one of those patent-ineligible concepts.”61 If, however,
there are no markedly different characteristics, the eligibility inquiry
continues onto the second step. The second step of the Alice framework is
to determine whether the claim recites any additional elements that
transform the nature of the claim into a patent eligible application.62 There
needs to be an inventive concept sufficient to show that the claim
“amounts to significantly more” than the judicial exception itself.63 In
determining if there is an inventive concept, all the claim elements must be
considered “both individually and in combination.”64 Examples of
“significantly more” include: transformation or reduction of a particular
article to a different state or thing,65 other meaningful limitations beyond
generally linking the use of the judicial exception to a particular
technological environment,66 or adding a specific limitation other than
what is well-understood, routine, conventional activity in the field, or
adding unconventional steps.67
Products encompassing a product derived from natural sources are

59 Id. at 577.
60 Alice Corp. Pry. v. CLS Bank Int'l, 573 U.S. 208, 217–18 (2014) (stating that the claims
were directed to a computerized process to mitigate settlement risk. The claims at issue dealt
exclusively with utilizing the method, a computer system to carry out the method, and
software for performing the method. The Supreme Court asserted that certain claims
involving computer software constituted ineligible subject matter under section 101 of the
Patent Act.).
61 Id. at 217.
62 Id. at 221.
63 Id.

64 Id.

65 Diamond v. Diehr, 450 U.S. 175, 184 (1981).

66 Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057, 1066–68 (Fed. Cir. 2011)

(describing an immunization step that integrates an abstract idea of data comparison into a
specific process of immunizing that lowers the risk that immunized patients will later develop
chronic immune-mediated diseases).
67 BASCOM Global Internet Serv. Inc. v. AT&T Mobility LLC, 827 F.3d 1341, 1350–51 (Fed.
Cir. 2016) (discussing a non-conventional and non-generic arrangement of various computer
components for filtering Internet content).
110 New England Law Review [Vol. 53

analyzed more closely under the first step.68 Nature-based products must
possess “markedly different characteristics” from any found in nature in
order to be patent eligible.69 If the nature-based product limitation has
markedly different characteristics when compared to its naturally-
occurring counterpart found in its natural state, the patent claim at issue is
patent eligible under § 101.70 Types of characteristics to consider when
determining “markedly different characteristics” include, but are not
limited to, the following: biological functions or activities, chemical and
physical properties, phenotype, and structure and form. 71

VI. Current Patents on Xenotransplantation

A. Genetic-Modified Animal

Despite the rising bar to patent eligibility, the United States Patent and
Trademark Office (USPTO) continues to issue patents to
xenotransplantation-related inventions. Currently, patents have been
assigned to inventions covering creating transgenic animals with knockout
genes. For example, US 8,034,330 B2 on multitransgenic pigs for diabetes
treatment provides certain animals, and in particular porcine animals;
tissue and cells derived from these, which lack any expression of functional
alpha 1.3 galactosyl transferase (CGT) and express one or more additional
transgenes which make them suitable donors for pancreatic islet. US
patent 8,034,330 B2 is on modified organs and cells for xenotransplantation.
Animals or cells are engineered or treated enzymatically in vitro to remove
the Gal epitopes and NeuGc epitopes, and to replace the NeuGc epitopes
with NeuAc, thereby protecting them from destruction by antibody
directed against the carbohydrate epitopes, and yet maintaining their
structural integrity and viability. US patent 10,278,372 on a genetically
modified pig comprising an exogenous polynucleotide encoding a human
leukocyte antigen G (HLA-G) polypeptide, and wherein the genetically
modified pig further comprises a disruption in a gene encoding a
glycoprotein galactosyltransferase alpha 1, 3 (GGTA1).
The common point of these patents is that some genes of the animal
(usually a pig) have been modified,72 creating a transgenic animal, and is

68 Deborah Ku, The Patentability of the CRISPR-CAS9 Genome Editing Tool, 16 CHI.-KENT J.

INTELL. PROP. 408, 429 (2016).

69 See MPEP at § 2106.04(c) (discussing the different characteristics when a claim recites a

natural-based product limitation).

70 Id.
71 Id.
72 See generally Genetics Generation, Transgenic Organisms, https://perma.cc/C9WN-S5RY

(last visited Oct. 28, 2019) (explaining that while chimeric organisms possess two genetically
distinct populations of cells, transgenic organisms consist of only one genetically distinct
population of cells that have been altered by the introduction of DNA sequences from sources
2019] 99% Human and 1% Animal? 111

claimed to lower rejection once an animal’s organ is transplanted into a

human recipient. Aside from the animal itself, the patents also claimed
extracted cells, tissues, and organs. These animals, when compared with
the natural counterparts do possess characteristics that are different.
Hence, one can argue that under the “markedly different” standard, these
inventions are patent eligible. In fact, in 1988, the USPTO issued the first
patent for a transgenic animal known as the “Harvard Oncomouse,” a
mouse in which a human oncogene has been injected into the germ cells of
the mouse that made it particularly disposed to breast cancer. 73 Since then
the USPTO has granted numerous patents for animals not occurring in
nature and with human genes. 74 As the Supreme Court’s decision in Myriad
shows, demonstrating that an invention does not occur in nature is a low
bar, a patent applicant only needs to show that the invention does not
specifically occur in nature.75

B. Human Stem Cells in Genetic-Modified Animal

The issue of creating genetically modified animals is that there is no

agreement as to the extent of gene editing needed to prevent rejection post-
transplantation.76 Hence, IBC has been introduced to use the patient’s own
stem cells in growing organs in animals, thus forming a human/nonhuman
chimeric embryo.77 There are various other reasons why researchers are
adopting to this new method in creating organs using human stem cells.
Under current strategies for obtaining cells and tissues from human stem
cells based on in vitro differentiation, there are several limitations. The most
important one is that the differentiation protocol are not amenable for the
generation of three-dimensional transplantable tissues and organs. 78

external to the organism).

73 Douglas Hanahan, Erwin F. Wagner & Richard D. Palmiter, The Origins of Oncomice: A

History of the First Transgenic Mice Genetically Engineered to Develop Cancer, 21 GENES DEV. 2259,
2267 (2007).
74 E.g., U.S. Patent No. 6,639,122 (filed Sept. 19, 2000) (on a transgenic swine having a

transgene encoding a human HLA-DQ or HLA-DR); U.S. Patent No. 7,141,716 (filed Aug. 20,
2002) (describing a pig’s organs and cells, where a preferred embodiment of the transgene
encodes a human protein).
75 See Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 595 (2013).
76 Waltz, supra note 17, at 1136.
77 Waltz, supra note 17, at 1136; See generally Jonathan D. Moreno, Why We Need to Be More

Accepting of 'Humanized' Lab Animals, ATLANTIC (Oct. 4, 2011), https://perma.cc/L9BH-3RYJ

(explaining that “human-animal chimera” is the term used to describe a mixture of cells or
tissues originating from a human and a non-human animal source and describing how
human-animal chimeras are instrumental in a variety of biomedical research efforts, including
our understanding of certain diseases).
78 Jun Wu et al., Generation of Human Organs in Pigs via Interspecies Blastocyst
Complementation, 51 REPROD. DOM. ANIM. 18, 19 (2016).
112 New England Law Review [Vol. 53

Researchers have admitted that through millions of years of evolution,

nature has established robust developmental program for each organism.
By taking advantage of these conserved developmental programs,
researchers may consider differentiating human PSCs in an in vivo
environment of an animal host. Complex tissues and organs are routinely
formed in vivo, and in vivo differentiation is highly synchronized and
guided by spatiotemporal dynamic development signals, meaning
embryonic cells know exactly where to go and what to become. 79 By
creating human/nonhuman chimera, this method raised the question of
whether this will fall under the meaning of directing to or encompassing
human organism under § 33(a) of AIA.80
Under AIA, “human organism” should exclusively include human
embryos, human/non-human chimeras, human fetuses, and human
beings.81 But how much human cells are needed in order to be categorized
as a human organism? USPTO has, before the passage of AIA, refused a
patent on the Newman-Rifkin application which tried to claim for chimeric
human/nonhuman animal embryos, cell lines, and fully developed animals
thereof, and descendants of such fully developed animals, human-animal
chimeras that could be up to 50% human. The USPTO rejected their patent
application because the broadest reasonable interpretation of the claimed
invention, the human-animal chimeras, encompassed a human being.82
However, the USPTO did not explain whether the claimed chimeras, which
could be at most 50% human, embraced a human being or distinguished
transgenic animals containing human genetic material and why such
transgenic animals do not embrace a human being.83 In the end, the USPTO
does not provide any standards for determining whether a creature is an
animal or human based on the percentages of animal and human cells it
contains.84

C. US Patent 10,335,263 B2

Although the USPTO has not established a standard on the percentage

of human cells needed in order to distinguish between a human and an
animal, one patent issued on July 2, 2019, composing of 90% to 99% human

79 Wu et al., supra note 78, at 19.

80 Leahy-Smith America Invents Act, Pub. L. No. 112-29 § 33(a), 125 Stat. 284, 340 (2011).
81 See America Invents Act, 157 CONG. REC. E1178 (daily ed. June 23, 2011) (statement of

Rep. David Weldon).

82 Chimeric Embryos and Animals Containing Human Cells, U.S. Patent No. 8,993,564 at p.

7 (filed Mar. 24, 1988) (final rejection letter issued on Oct. 28, 1999).
83 Ryan Hagglund, Patentability of Human-Animal Chimeras, 25 SANTA CLARA COMPUTER &
HIGH TECH. L.J. 51, 68 (2008).
84 Yvonne Cripps, The Global Person: Pig-Human Embryos, Personhood, and Precision Medicine,

25 IND. J. GLOBAL LEGAL STUD. 701, 717 (2018).

2019] 99% Human and 1% Animal? 113

cells inside a pig kidney further adds to the ambiguity on what constitutes
a human organism. US patent 10,335,263 B2 claimed for organs (kidney) for
transplantation. The kidney is a complex organ with multiple cell types
and a complex functional anatomy that renders it one of the most difficult
to reconstruct. In this invention, the inventors claimed that a kidney for
transplantation can be manufactured using two methods. 85 In the first
approach, the human mesenchymal stem cells86 or kidney stem cells are
transplanted to a fetus in a pregnant mammalian host. The mesenchymal
stem cells or kidney stem cells can be directly transplanted to the fetus in
vivo, thereby forming a kidney in the uterus as they are to be grown into a
kidney for transplantation.87
In the second approach, the uterus is separated from a parent body,
and the human mesenchymal stem cells are transplanted to a specific organ
location of the fetus separated from an outer layer and then cultured in a
culture bottle for the whole embryo culture in vitro. Injecting of GDNF-
transferred hMSCs into embryos followed by relay culture enables the
generation of chimeric organ. After a predetermined culture time, the
resulting product is evaluated for transplantation. The product may be
transplanted to the greater omentum of an animal.88 After transplantation,
the organ for transplantation is continuously grown in vivo, and thus the
formation of a replicated kidney exhibits a kidney function.
In both methods, the goal is to compose the organ with 90% to 99%
human cells derived from the recipient’s own bone marrow, circulating
blood, or umbilical cord blood. The host animal is also genetically modified
to induce death of animal cells to avoid mixing with human cells. The
interesting part is with 90% to 99% human cells inside the kidney and
roughly 10% to1% porcine cells used as a scaffold for the organ, provides

85 See generally Takashi Yokoo et al., Human Mesenchymal Stem Cells in Rodent Whole-Embryo
Culture are Reprogrammed to Contribute to Kidney Tissues, 102 PNAS 3296 (2005); Takashi Yokoo
et al., Xenobiotic Kidney Organogenesis form Human Mesenchymal Stem Cells Using a Growing
Rodent Embryo, 17 J. AM. SOC. NEPHROL. 1026 (2006).
86 See generally Imran Ullah, Raghavendra Barengundi Subbarao & Gyu Jin Rho, Human

Mesenchymal Stem Cells – Current Trends and Future Prospective, BIOSCIENCE REP. 35 (2015)
(“Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and
animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells
with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and
chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes).”).
87 Sylvia Pagán Westphal, Growing Human Organs on the Farm, NEW SCIENTIST, (Dec. 20,
2003), at 4 (explaining that chimerism in chimeras created by this method is of a lesser extent
than in those created by the fusion method, and cells derived from the injected cells are
usually restricted to certain organs and/or are present in small numbers).
88 See generally Krithika Hariharan, Andreas Kurtz & Kai M. Schmidt-Ott, Assembling

Kidney Tissues from Cells: The Long Road from Organoids to Organs, FRONTIERS IN CELL AND
DEVELOPMENTAL BIOLOGY 3 (2015) (explaining that the chimeric organ is transplanted to the
omentum to facilitate vascularization of the developing neo-organ).
114 New England Law Review [Vol. 53

one extreme example of human/non-human chimera. This is also the target

for United Therapeutics which aims to produce organs having the scaffold
of a pig’s lungs, but all the cells will be human. 89 By granting a patent, this
invention contradicts the USPTO’s earlier position in Newman-Rifkin
patent application, in which it stated that, a chimeric organism may be
obviously non-human in an extreme case (e.g. 99% non-human cells, 1%
human cells) and of ambiguous humanity in other cases (50% human cells,
50% non-human cells).90
The USPTO’s ignorance on the amount of human cells could be based
on these following reasons: first, Mesenchymal stem cells do not have the
potential to develop into a human being but rather specific organs; second,
this invention only uses the embryo of the host to develop the fetus rather
than allowing the chimera to be created inside the uterus in vivo; third, the
development of the kidney is within the whole embryo culture and organ
culture in vitro first and then relocate to the omentum of the recipient for
further development; and fourth, unlike transgenic animals, this invention
involves chimerism but also unlike IBC, this invention solely focuses on the
creation of the kidney rather than human/nonhuman chimera. Hence,
despite the extremely high number of human cells presented, no human
being or human/nonhuman chimera has been created. By granting the
patent, the USPTO seems to go beyond the percentage of human cells
argument in the Newman-Rifkin patent application. This suggests the
amount or percentage of human cells presented might not be the sole
criteria in considering whether an invention is a human organism under §
33 (a) of AIA.

VII. Interspecies Blastocyst Complementation

A. Current Patent Applications

Currently, the few patent applications on IBC are all filed by pioneers
in the field. For example, US2014/0338008 A1 claimed a method of organ
regeneration utilizing human iPSC and blastocyst complementation. This
application claims a method for producing a target organ, using human
iPSC in a living body of a non-human mammal having an abnormality
associated with a lack of development of the target organ in a
development, the target organ produced being derived from a different
individual mammal that is an individual different from the non-human
mammal. The other application US2017 / 0283777 A1, claims both the
chimeric mammals and organs derived from chimeric mammals cultured

89 Koebler, supra note 23.

90 See generally Seán M. Coughlin, The Newman Application and the USPTO’s Unnecessary
Response, 5 CHI.-KENT J. INTELL. PROP. 90 (2006).
2019] 99% Human and 1% Animal? 115

using methods of mammalian chimeric complementation.

Unlike the transgenic animals discussed earlier, the chimeric mammals
described here are mammals comprising cells derived from a first mammal
and a second mammal. The cells from the first mammal comprise cells
derived from a blastocyst containing a genetic modification at one or more
loci, and the cells from the second mammal contain cells derived from a
naïve like induced pluripotent stem cell91 and form at least one organ or
tissue, wherein the first and second mammal are different species. The
chimeric mammal has a percentage of chimerism at a ratio of between less
than 10% to at least 99%. The organs which could be isolated from the
chimeric mammal are comprised of liver, kidney, pancreas, hematopoietic
stem cells, spleen, bone marrow, heart, lung, skin, cornea, eye, spinal cord,
uterus, intestine, heart valve, bone, cartilage, tendon, ligament, lymphatic
vessel, and blood vessel.

B. Patent Eligibility Inquiry for Organs from IBC

IBC is a novel approach in creating organs for humans. It is a different

technology in comparison to the patents illustrated earlier. First, IBC uses
human iPSC instead of adult stem cells. Second, human iPSC is injected
into a genetically modified pig embryo and the chimeric animal is allowed
to develop inside the embryo in vivo until the organ is ready for
transplantation. Like U.S. patent 10,335,263 B2, the goal is to create an
organ with predominately human cells. Scientists have successfully
achieved this in mice/rat chimeras by injecting mice iPSC into rat
blastocysts that lacked genetic materials for generating a pancreas. The rats
then developed normally except that their pancreases were 99% mouse. 92
As mentioned earlier, currently, two major obstacles in IBC include finding
the chimeric capable human iPSC and matching the differences in the
developmental speed between species.93
The use of human iPSC could create both legal and ethical issues. First,
unlike U.S. patent 10,335,263 B2, human iPSCs can create the ability to
genetically reprogram somatic cells into a pluripotent state, which may
allow them to differentiate into other types of cells including eggs and
sperm that can be used to create new organisms. In other words, human
iPSCs may be able to give ordinary somatic body cells the same “potential
for human life” as naturally produced embryos and gametes.94 Second,

91 See, e.g., Joseph Caputo, Scientists Use Stem Cells to Create Human/pig Chimera Embryos,

EUREKALERT! (Jan. 26, 2017), https://perma.cc/URV5-X7BA (explaining that naïve cells

resemble cells from an earlier developmental origin with unrestricted developmental
potential).
92 Waltz, supra note 17, at 1136.
93 See De Los Angles, supra note 33.
94 Osagie K. Obasogie & Helen Theung, Moore is Less: Why the Development of Induced
116 New England Law Review [Vol. 53

some argued that human iPSCs should not be introduced into early-stage
non-human primate embryos because at those very early stages, it is not
clear where the cells will go and it is possible that the cells will find their
way to animal brains.95 This fear is founded on the belief that the process of
injecting human cells into an animal blastocyst has the potential to produce
a chimera with a human-like nerve system that is capable of producing
human consciousness.96 Third, unlike chimeras, transgenic animals and
cells do not display a significant amount of human characteristics, but a
chimera containing a sufficient percentage of human cells might resemble a
human.97
Although federal laws do not restrict the creation of part-human
chimeras, the National Institutes of Health has issued a moratorium on
federal funding for human-animal chimera research as it considers ethical
issues associated with the introduction of human stem cells to animal
embryos. The National Academy of Sciences has recommended subjecting
part-human chimera research to specialized review in cases where there is
a significant possibility that human pluripotent stem cells will contribute to
neural or gamete cells and tissues,98 while bills introduced (but not passed)
in the Senate in 200599 and in the House in 2016100 would have prohibited

Pluripotent Stem Cell Lead Us to Rethink Differential Property Interests in Excised Human Cells, 16
STAN. TECH. L. REV. 51, 52 (2012).
95 Waltz, supra note 17, at 1137.
96 Benjamin Capps, Do Chimeras Have Minds? The Ethics of Clinical Research on a Human–
Animal Brain Model, 26 CAMBRIDGE Q. HEALTHCARE ETHICS 577 (2017).
97 Hagglund, supra note 83, at 82–83.

98 National Research Council and Institute of Medicine. 2010. Final Report of the National

Academies’ Human Embryonic Stem Cell Research Advisory Committee and 2010 Amendments to the
National Academies’ Guidelines for Human Embryonic Stem Cell Research. Washington, DC: The
National Academies Press.
99 Human Chimera Prohibition Act, S.1373, 109th Cong. (2005).

100 Human-Animal Chimera Prohibition Act of 2016, H.R. 6131, 114th Cong. § 1131 (2016)

(“The term ‘human-animal chimera’ means—

(A) a human embryo into which a nonhuman cell or cells (or the
component parts thereof) have been introduced to render the embryo’s
membership in the species Homo sapiens uncertain;
(B) a chimera human/animal embryo produced by fertilizing a human
egg with nonhuman sperm;
(C) a chimera human/animal embryo produced by fertilizing a nonhuman
egg with human sperm;
(D) an embryo produced by introducing a nonhuman nucleus into a
human egg;
(E) an embryo produced by introducing a human nucleus into a
nonhuman egg;
(F) an embryo containing at least haploid sets of chromosomes from both
2019] 99% Human and 1% Animal? 117

the creation of several kinds of part-human chimeras, including chimeras

whose neural tissues are predominantly human. As chimeras possess some
cells that are completely human, it could be possible to create a chimera
that has the body and outward appearance of an animal but the brain and
central nerve system of a human.101 Nonetheless, US2014/0338008 A1 is a
bold challenge to AIA § 33 (a), since it is claiming on the human/nonhuman
mammal itself.

C. Markedly Different

Organs generated via IBC require the use of human or animal

biological materials as the raw material and as the final product. Thus, the
invention will be tested under the current Mayo-Alice standard to assess for
patent eligibility. Under Product of Nature Doctrine, for an invention
derived from nature to be patentable, the inventor’s work must result in a
transformation giving rise to a “new and different article having a
distinctive name, character, or use . . . .”102 According to USPTO’s MPEP
2106.4 (c), appropriate characteristics could be expressed as the nature-
based product structure, function, and/or other properties. When
evaluating characteristics to determine “markedly different,” a
characteristic must be changed as compared to the nature, and cannot be
an innate characteristic of the naturally occurring counterpart or an
incidental change in the characteristic of the naturally occurring
counterpart.103
Organs generated via IBC could satisfy this requirement since chimeric
organs do not exist in nature and are made by man. Furthermore, animal
organs may have different sizes than human organs. As indicated in the
patent publication of 10,335,263 B2, if the organ is a kidney, it is not
necessary that it be the same size, and as long as it has one tenth of the
kidney function, dialysis can be sufficiently performed and a life can be
sufficiently maintained. One could genetically edit the patient’s iPSC
before injecting them into a blastocyst and correct a genetic disease, such as
polycystic kidney disease.104 Furthermore, even if generating a human

a human and a nonhuman life form;

(G) a nonhuman life form engineered such that human gametes develop
within the body of a nonhuman life form; or
(H) a nonhuman life form engineered such that it contains a human brain
or a brain derived wholly or predominantly from human neural
tissues.”).
101 Thomas A. Magnani, The Patentability of Human-Animal Chimeras, 14 BERKELEY TECH. L.J.

443, 450 (1999).

102 Hartranft v. Wiegmann, 121 U.S. 609, 615 (1887).
103 See Myriad, 569 U.S. at 2111.
104 Graziano Oldani et al., Xenogenic Chimera-Generated by Blastocyst Complementation-As A
118 New England Law Review [Vol. 53

organ in an animal is successful, the vascular systems will still be

contributed by the animal.105 Researchers could knock out the entire
vascular system inside the pig organ and fill the niche with human cells
hoping to give a donor organ a human vasculature.106 Hence, applicants
claiming for IBC generated organs should be able to satisfy the USPTO’s
requirement to have caused the claimed product to possess at least one
characteristic that is different from that of the natural counterpart. 107

D. Directed to or Encompassing a Human Organism

By claiming the human/nonhuman chimera, organs generated from

IBC might face obstacles to meet § 33 (a) of AIA. If an invention is
considered a human organism, it will not be patent eligible even with
markedly different characteristics such as a transgenic human being.108 As
mentioned earlier, under AIA, “human organism,” should exclusively
include human embryos, human/non-human chimeras, human fetuses, and
human being. However, AIA fails to define what it means, at least for
patent purposes, to be human.109 AIA has also failed to define to what
extent human/nonhuman chimera will be considered a human organism.
The word “human” can be defined in many ways. For example, “human
organism” could be understood to mean “any living entity containing one
or more cells belonging to the species Homo Sapiens,”110 it might also refer
to someone who possess characteristics unique to members of the human
species, such as sentience and feelings of shame, or a chimera containing a
sufficient percentage of human cells might resemble a human. 111
Recommendations from the Academy of Science and the bills
introduced in both the House and the Senate seem to concentrate on
whether a human will be created as a result (focuses on gamete cells) and
whether the creature will have human consciousness (focuses on neural

Potential Unlimited Source of Recipient Tailored Organs, 24 XENOTRANSPLANTATION 1, 4 (2017).

105 Waltz, supra note 17, at 1137.

106 Waltz, supra note 17, at 1137 (explaining that otherwise an organ developed in an

animal host would contain xenogeneic blood vessels, which in turn would be targeted by the
host immune system).
107 Ex parte Allen, 2 U.S.P.Q.2d 1425, 1426 (Bd.Pat.App. & Interf. 1987) (determining that

whether a living thing was patentable “is simply whether that subject matter was made by
man.”).
108 Hagglund, supra note 83, at 57.
109 Yaniv Heled, On Patenting Organisms or How the Abortion Wars Feed into the Ownership
Fallacy, 36 CARDOZO L. REV. 241, 260-61 (2014).
110 Ava Caffarini, Directed to or Encompassing a Human Organism: How Section 33 of the
America Invents Act May Threaten the Future of Biotechnology, 12 J. MARSHALL REV. INTELL. PROP.
L. 769, 781 (2013).
111 Hagglund, supra note 83, at 83.
2019] 99% Human and 1% Animal? 119

cells).112 Despite these suggestions, it is unlikely legislators, courts, and

patent examiners will soon arrive at a consensus. As stated earlier, the
USPTO does not use percentage of human cells as the sole indicator in
judging patent eligibility. Rather, the USPTO also takes the following
criteria into consideration: the type of stem cells used; whether the
invention involves developing the organism in the uterus in vivo; and
having the potential of becoming a human or human being itself.

E. Biological and Technical Solutions to Ethical Dilemma

It is our brain that makes us human. 113 Therefore, it is crucial to

determine whether injection of human iPSC into animal blastocyst would
humanize the animal brain. Biologically, it is unlikely that animals will
develop human consciousness, as neutral progenitor cells need more time
to develop and go through many more divisions and result in larger brains
in primates than in most other animals. 114 Humanization of animal bearing
human organs could also result in the production of human gametes and
human embryo could thus be created using such gametes. However, the
possibility that the interaction between gametes of different species would
result in a hybrid embryo is almost nonexistent due to the interspecies
reproductive barrier.115 Although similar in physiology and organ size, the
evolutionary distance between human and pig is even greater than that
between human and mouse.116 High percentage of all-body chimerism
leads to embryonic development impairment and abortion.117 Even if
development is possible, another method which could also prevent the
production of gametes is simply to sterilize the animal host. 118
Technically, several ways can be used to limit the risks above. For
example, human iPSC will only be used for complementation, replacing
cells/tissues that are absent as a consequence of knock-out. Researchers

112 Stephen R. Munzer, Human-Nonhuman Chimeras in Embryonic Stem Cell Research, 21

HARV. J. L. & TECH. 123, 132–33 (2007) (categorizing cognitive level of human/non-human
chimera into three categories: (1) Basic human-nonhuman chimeras do not have cognitive
capacities higher than those of a dog or a pig; (2) Enhanced human-nonhuman chimeras have
cognitive capacities roughly equivalent to those of a chimpanzee; and (3) dramatically
enhanced human-nonhuman chimeras have cognitive capacities- including intelligence,
linguistic capacity, self-awareness, emotions, and the ability to form and maintain social
relationships that approximate the capacities of a human being).
113 Andrew Moore, The UK’s Guidelines on Animals Containing Human Material: Another
Trailblazing Performance in Science PR: It’s an Admirable Start, but the Problem Will Lie in the Grey
Area, 33 BIOESSAYS 649 (2011).
114 Bourret, supra note 22, at 90.
115 Bourret, supra note 22.
116 Wu, supra note 4.

117 See Wu, supra note 4.

118 See Wu, supra note 4.

120 New England Law Review [Vol. 53

have also demonstrated that human iPSC differentiation can be restricted

to certain tissues to prevent the cells from integrating unwanted organs
such as the brain or ovaries.119 Furthermore, injected human iPSC could be
genetically modified through the significant increase gene editing
efficiency such as CRISPR to render them incapable of differentiating into
neural and gametes cells.120 CRISPR enables researchers to target specific
sequences of DNA, thereby controlling what genes are expressed and
preventing the unintended imposition of undesirable characteristics.121
Injected human iPSC could also include suicide genes to inhibit their
differentiation into neural or gametes. 122 By preventing the possibility of
becoming too “humanized,” the chimera serves merely as an incubator for
artificial organs. Therefore, organs generated via IBC should satisfy both
markedly different tests and would not be considered as human organism.

VIII. Counterarguments for Patent Eligibility Inquiry for Organs

from IBC

Under the current 35 U.S.C. section 101 and AIA section 33(a), organs
generated via IBC seem to comply with the patent eligibility requirements.
However, counterarguments could still be made on whether those organs
are truly product of man rather than product of nature. With the advances
in technology, researchers are capable of using various ways in creating
artificial organs to address the need of organ shortage. As stated earlier, the
goal is to not to create an exact replica of the organ, but to create organs
that are functionable and compatible with the patient once transplanted
which will not trigger immune rejection.
The Supreme Court in Mayo stated that “all inventions at some level
embody, reflect, rest upon, or apply laws of nature, natural phenomena, or
abstract ideas.”123 As stated in Ariosa Diagnostics, Inc. v. Sequenom, Inc.,124
only an innovative or inventive use of a natural phenomenon may be
patentable. It is therefore essential to delineate what is the actual invention
and what is the work of nature within an invention. Unlike an organ
generated via IBC, however complicated, human intervention is akin to the
preparation process, while the development of the organ is still within the
realm of nature, that is, within the body of the host animal following the

119 Toshihiro Kobayashi et al., Targeted Organ Generation Using Mix1-Inducible Mouse

Pluripotent Stem Cells in Blastocyst Complementation, 24 STEM CELLS AND DEV. 182, 182 (2015).
120 Wu, supra note 38, at 90–91.
121 Jian Cao et al., An Easy and Efficient Inducible CRISPR/Cas9 Platform with Improved
Specificity for Multiple Gene Targeting, 44 NUCLEIC ACIDS RES. 1, 9 (2016).
122 Bourret, supra note 22, at 4.

123 Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct 1289, 1293 (2012).

124 Ariosa Diagnostics, Inc. v. Sequenom, Inc., 19 F.Supp. 3d 938, 950 (N.D. Cal. 2013)

(quoting Myriad Genetics, 133 S. Ct. at 2119).

2019] 99% Human and 1% Animal? 121

blue print nature has designed through evolution. The preparation process
might be complicated, but as stated in Myriad, the detail of the extensive
process of discovery is not sufficient to satisfy section 101,125 especially
when the claim is directed to the chimeric human/nonhuman animal or the
isolated organ. Hence, even if patent eligible, it should be directed to the
method instead of the product.
Furthermore, these artificial organs serve the same function as their
natural counterpart, to work holistically with other organ systems and to
sustain the life of the patient. Similarity in function is one of the reasons
why Dolly the sheep is patent ineligible because the inventors “‘did not
create or alter any of the genetic information’ of its claimed clones.”126 In Re
BRCA1, BRCA2, the Federal Circuit states the “naturally occurring
sequences at issue here do not perform a significantly new function.”127 “A
DNA structure with a function similar to that found in nature can only be
patent eligible as a composition of matter if it has a unique structure,
different from anything found in nature.”128 Even when one argues that
organs generated via IBC are markedly different from the natural organ. A
patentee could turn to nearly any characteristics to prove the existence of
“markedly different,” even if the marked difference is not important to the
purpose of the invention.129 The question for markedly difference is to the
type and degree needed. As Learned Hand eloquently stated in 1911, there
is a “line between different substances and degrees of the same
substance.”130

IX. Ways Forward for Organs via IBC

In order to foster the healthy development of IBC and the generation of

industry based on it, it is vital that patent law serve to promote and protect
the benefits of medical research. The recognition of genetic-modified
bacteria as patent eligible in Chakrabarty was widely recognized as a “key

125 Myriad, 133 S. Ct. at 2110.

126 In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337 (Fed. Cir. 2014) (quoting Assn. for
Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 577 (2013)) (indicating that Dolly the
cloned sheep is an exact genetic replica of another sheep and does not possess ‘‘markedly
different characteristics from any farm animals found in nature”).
127In re BRCAl- and BRCA2- Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 760–
61 (Fed. Cir. 2014).
128 Id. at 761.
129 See Assn. for Molecular Pathology v. U.S. Pat. and Trademark Off., 702 F. Supp. 2d 181,
226 (S.D.N.Y. 2010), as amended (Apr. 5, 2010), aff'd in part, rev'd in part, 653 F.3d 1329 (Fed. Cir.
2011), cert. granted, judgment vacated sub nom. 566 U.S. 902 (2012), and opinion vacated, appeal
reinstated, 467 Fed. Appx. 890 (Fed. Cir. 2012) (unpublished), and aff'd in part, rev'd in part, 689
F.3d 1303 (Fed. Cir. 2012).
130 Parke-Davis & Co. v. H.K. Mulford Co., 189 F. 95, 103 (S.D.N.Y. 1911), aff'd in part, rev'd

in part sub nom. 196 F. 496 (2d Cir. 1912).

122 New England Law Review [Vol. 53

factor in spurring the explosive growth in the biotech industry” in the

US.131 The Chakrabarty Court’s paved the way for dramatic advances in the
life sciences and in medical treatment.132 Similarly, patent law should serve
the need of nascent technologies such as IBC. As discussed in this article,
current patent jurisprudence seems to support the patenting of organs
generated via IBC. However, counter arguments could also be made that
the markedly different test is a low bar and organs generated via IBC could
only claim for the method instead of the product itself.
However, these arguments are not new and could similarly be made
against the patenting of transgenic animals. Likewise, researchers in
Oncomouse did not create the mouse but inserted onco genes into the
mouse, but that does not stop the USPTO for granting the inventors a
product patent. Furthermore, although the process of producing the
human/nonhuman chimera is within the uterus of the host animal, the
generation of the organ is not entirely a natural process without human
intervention. Human intervention is needed to create a niche of the organ
desired, to knock out the possibility of growing gamete and neural cells,
and to knock out the vascular system. In this sense, the growing of the
chimera is a part of the invention, but it is not the end as the organ isolated
will then have to be transferred to the patient to further the growth of
vascular system.133 The entire process is a product of man rather than
nature.
Thus, it is important to note that with the progress of gene-editing
tools and other technologies many of the ethical arguments previously
made against the creation of human/nonhuman chimera and or directing
or encompassing human could be outdated. As seen in this article,
percentage of human cells once discussed in Neman-Rifkin is no longer a
concern, and no one will argue an organ with 99% human cell is a human.
As mentioned earlier, current technology is capable of eradicating the
possibility of iPSC to different neural cells through genetic modification or
to introduce suicide genes.134 Ironically, preventing human cells from
migrating into the brain is actually the easy part; a more challenging part is
getting animal cells to proliferate in animals in the first place.135 The
ambiguous prohibition of human/nonhuman chimera in AIA might be too
restrictive and needs a liberal interpretation. In addition,
human/nonhuman chimera does not need to bring to term such as in the

131 See ROBERT MERGES & JOHN DUFFY, PATENT LAW AND POLICY 98 (7th ed. 2017).
132 Madigan & Mossof, supra note 48, at 943.
133 See generally Joydeep Basu & John W. Ludlow, Platform Technologies for Tubular Organ

Regeneration, 28 TRENDS BIOTECHNOLOGY, 526(2010).

134 See Tamir Rashid et al., Revisiting the Flight of Icarus: Making Human Organs from PSCs

with Large Animal Chimeras, 15 CELL STEM CELL 406, 409 (2014).
135 Waltz, supra note 17, at 1137.
2019] 99% Human and 1% Animal? 123

example of kidney, as one tenth of the size will be adequate to achieve its
purpose, thereby preventing the full development of the
human/nonhuman chimera. IBC is not the first case in which the law fails
to keep up with technology advances, but it is important that patent law
continues to act as an incentive like it did in Chakrabarty; as Jefferson once
famously stated, “innovation should receive a liberal encouragement.”136

CONCLUSION

Development of IBC technology has shed light on patients in need of

organ transplant. When such need arises, often it is urgent, but to have an
organ ready and compatible at the right time is often impossible. However,
with advances in regenerative medicine, researchers not only are able to
create artificial organs but also can allow them to be patient specific. While
the organ created via IBC could satisfy the “markedly different” test, it
might be barred by AIA § 33(a) for human/nonhuman chimera, which is
patent ineligible as encompassing or directing to a human organism.
However, as argued in this article, human/nonhuman chimera is no longer
taboo. Gene editing tools and various available technologies could
eliminate much of what one considers as human characteristics while
maintaining those relevant traits for developing an organ. By using
human/nonhuman chimera as organ incubators, the creation is the
chimeric organ rather than a “parade of horribles.”137 However, much
concern regarding human/nonhuman chimeras fails to stand under the
currently available technologies, and patent law, should reflect according
to technological change.

136 Diamond v. Chakrabarty, 447 US 303, 308 (1980) (quoting Thomas Jefferson,
Correspondence, in 5 Writings Of Thomas Jefferson 75, 76 (H. A. Washington ed., 1871) vol. 5,
75–76.) (“The Act embodied Jefferson’s philosophy that ‘ingenuity should receive a liberal
encouragement.’”).
137 See id. at 316 (detailing a “parade of horribles” from Nobel Laureates and other

scientists about the dangers of biotech research, who argued that it should not be patentable).