THE BOARD OF REGENTS OF THE UNIVERSITY OF OKLAHOMA

Patent Trials and Appeals Board

Feb 20, 2020

14671322 - (D) (P.T.A.B. Feb. 20, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/671,322 03/27/2015 William H. Hildebrand OAKU.007A 5122
20995 7590 02/20/2020
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE, CA 92614
EXAMINER
DIBRINO, MARIANNE
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
02/20/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
efiling@knobbe.com
jayna.cartee@knobbe.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte WILLIAM H. HILDEBRAND,
CURTIS MCMURTREY, DAVID LEWINSOHN,
DEBORAH LEWINSOHN, and MELANIE HARRIFF
__________

Appeal 2019-005039
Application 14/671,322
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, CHRISTOPHER G. PAULRAJ, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to
trimolecular complexes of soluble, truncated HLA-E heavy chain, beta-2-
microglobulin, and particular peptides. The Examiner rejected the claims as
directed to non-statutory subject matter. We have jurisdiction under
35 U.S.C. § 6(b). We reverse.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the Real Parties in Interest as the
Board of Regents of the University of Oklahoma, the Oregon Health &
Science University, Emergent Technologies, Inc., and Pure Protein, LLC
(see Appeal Br. 2).
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Statement of the Case
Background of the Invention
“Mycobacterium tuberculosis (Mtb) is a pathogenic bacterial species
and the cause of most cases of tuberculosis (TB)” (Spec. ¶ 7). “The
identification of novel, Mtb-specific epitopes is a critical step in the
development of T cell receptor-mediated immunotherapeutics against TB”
(Id. ¶ 49).
The Specification explains that an infected person’s immune response
to TB begins when “[c]lass I [major histocompatibility complex (MHC)]
molecules alert the immune response to disorders within host cells” (Spec.
¶ 5). The immune system is alerted when proteins derived from the Mtb
bacteria are cleaved into peptides, and the cleaved peptides “are loaded into
the class I MHC molecule’s antigen binding groove in the endoplasmic
reticulum of the cell and subsequently carried to the cell surface” (id.).
“Once the class I MHC molecule and its loaded peptide ligand are on the
cell surface, the class I MHC molecule and its peptide ligand are accessible
to cytotoxic T lymphocytes (CTL)” (id.). The CTLs then “survey the
peptides presented by the class I MHC molecule and destroy those cells
harboring ligands derived from infectious . . . agents within that cell” (id.).
Among these class I MHC molecules, the Specification identifies and
discusses the “non-classical HLA-E complex,” which is “distinct from
classical HLA (such as HLA-A, HLA-B, and HLA-C) in that it is
monomorphic in the human population, as compared with the classical HLA
that are polymorphic” (Spec ¶ 8). “[A]ll people in the population tend to
have the same HLA-E on the surface of all their cells” (Id.).
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As potential biomarkers that could be used for targeted therapies, the
Specification discusses HLA-E/Mtb complexes that utilize soluble HLA
molecules created in vitro (Id. ¶ 25). Although the “HLA-E presented
peptides were purified and identified directly from infected cells,” the
Specification also indicates that such HLA-E/Mtb ligands described and/or
claimed in the present application “were not previously known to be
presented by the HLA-E of any infected cell” (Id.). “[S]ince HLA-E is
monomorphic, these targets can be applied to the entire human population”
(Id.). According to the Specification, “[t]he soluble HLA molecules that
enable direct comparative discovery of infected ligands do not exist in nature
-- these soluble HLA have been created in the laboratory. Therefore, the
soluble HLA/ligand complexes distinct to Mtb-infected cells disclosed
and/or claimed herein do not exist in nature” (Id.).
The Specification further discusses, as an inventive concept, a
“trimolecular complex” that includes: a) a soluble, truncated HLA-E heavy
chain that does not contain the transmembrane and cytoplasmic domains of
the native, full length HLA-E heavy chain, b) beta-2-microglobulin (β2m),
and c) an Mtb-specific peptide ligand (Spec. ¶ 38). The Specification
includes a table of peptides that are unique to Mtb-infected cells, among
which is listed a peptide with sequence EIEVDDDLIQK (SEQ ID NO: 27)
and identified as being derived from a “hypothetical protein” whose
sequence is found in the Mtb genome (Id. at 22).
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The Claims
Claims 1–6 and 11–16 are on appeal. Claim 1 is representative and
reads, in relevant part,2 as follows:
1. A composition, comprising at least one of: . . .
(p) an isolated class I HLA trimolecular complex
formed in vitro, the trimolecular complex comprising a soluble,
truncated HLA-E heavy chain, beta-2-microglobulin, and a
peptide consisting of SEQ ID NO: 27, and wherein the soluble,
truncated HLA-E heavy chain does not contain the
transmembrane and cytoplasmic domains of the native, full
length HLA-E heavy chain . . .[.]

The Rejection3
The Examiner rejected claims 1–6 and 11–16 under 35 U.S.C. § 101
as directed to non-statutory subject matter (Final Act. 2–4).
The Examiner finds claim 1, as elected, is “directed to a composition
comprising an isolated class I HLA-E trimolecular complex formed in vitro,
comprising a soluble, truncated HLA-E heavy chain, β2m, and a peptide
consisting of SEQ ID NO: 27” (Final Act. 2).
The Examiner finds the Specification discloses “that this HLA-E
complex was purified and identified directly from mycobacterial infected

2 The Examiner required a species election on July 28, 2017. We limit our
consideration of the merits of the appealed rejection to the elected species.
See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987). Thus, we read
the claims as limited to a complex of HLA-E/β2m and SEQ ID NO: 27
based on Appellant’s response filed Sept. 25, 2017. We only reproduce the
elected species in claim 1.
3 The Examiner withdrew rejection of some claims under 35 U.S.C. §§ 101,
112(a), and 112(b) based on entered after-final amendments (see Ans. 3–4).
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cells” (id. 3). The Examiner cites Ravindranath4 as teaching that “HLA-E is
ubiquitously transcribed in all human tissues, over-expressed and shed (i.e.,
wherein the heavy chain lacks the transmembrane and cytoplasmic domains
of cell surface bound HLA-E) into circulation upon inflammation” (id.).
The Examiner, therefore, finds that “the composition comprising the soluble
HLA-E/SEQ ID NO: 27 peptide complex has a natural counterpart in vivo
that is shed from HLA-E expressing, Mtb-infected cells” (id.).
The Examiner further finds that “the breaking of peptide bonds such
that a full length protein is truncated does not confer a marked structural
difference for the purpose of 35 USC [§] 101. In addition, the function of
both the soluble complex and the cell surface complex is to bind the cognate
receptor” (id.).
Appellant contends:
There is no evidence of record that supports the Examiner’s
theory of how the claimed compositions are found in nature. At
most, the Examiner has proposed the mere possibility that under
an unlikely and remote circumstance, the claimed compounds
could be made by a natural process. This is legally insufficient
to sustain a rejection under Section 101.
(Appeal Br. 13). Appellant cites to Example 8 of the Interim Guidance5
directed to a chimeric antibody that states “‘it is possible that nature might
randomly create a murine antibody having the CDR sequences of SEQ ID

4 Ravindranath et al., Anti-HLA-E mAb 3D12 mimics MEM-E/O2 in binding
to HLA-B and HLA-C alleles: Web-tools validate the immunogenic epitopes
of HLA-E recognized by the antibodies, 48 Mol. Immunol 423–30 (2011).
5 Links to both the Interim Guidance and Examples may be found at
https://www.uspto.gov/patent/laws-and-regulations/examination-
policy/subject-matter-eligibility.
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NOs: 7-12. But unless the examiner can show that this particular
murine antibody exists in nature, this mere possibility does not bar the
eligibility of this claim’” (id. 14, citing Interim Guidance at 12).
Appellant similarly contends that Ravindranath “shows no more than
the mere possibility that HLA-E can be solubly expressed under some
inflammation circumstances” (Appeal Br. 14). Appellant cites Coupel6 as
evidence that “soluble HLA-E is not found in normal sera, and thus under
normal circumstances HLA-E is not solubly expressed” (id. 15). Appellant
concludes that “[t]here is no evidence of record supporting the Examiner's
allegation that soluble HLA-E is naturally produced by Mtb-infected cells or
macrophages, and even if it was, that the soluble HLA-E would necessarily
be loaded with the specifically claimed peptides” (id. 16).
The Alice Test
The Supreme Court has long interpreted 35 U.S.C. § 101 to include
implicit exceptions: “[l]aws of nature, natural phenomena, and abstract
ideas” are not patentable. See, e.g., Alice Corp. v. CLS Bank Int’l, 573 U.S.
208, 216 (2014).
In determining whether a claim falls within an excluded category, we
are guided by the Supreme Court’s two-step framework, described in Mayo
and Alice. Id. at 217–18 (citing Mayo Collaborative Servs. v. Prometheus
Labs., Inc., 566 U.S. 66, 75–77 (2012)). In accordance with that framework,
we first determine if there is a judicial exception. Although composition of
matter claims are generally eligible subject matter, claims that are directed

6 Coupel et al, Expression and release of soluble HLA-E is an
immunoregulatory feature of endothelial cell activation, 109 Blood 2806–14
(2007).
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only to laws of nature and/or natural phenomena are directed to patent
ineligible concepts. Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d
1371, 1376 (Fed. Cir. 2015).
If the claim is “directed to” a judicial exception, we turn to the second
step of the Alice and Mayo framework, where “we must examine the
elements of the claim to determine whether it contains an ‘inventive
concept’ sufficient to ‘transform’ the claimed abstract idea into a patent-
eligible application.” Alice, 573 U.S. at 221 (quotation marks omitted).
2019 Guidance
The United States Patent and Trademark Office published guidance
on the application of 35 U.S.C. § 101. USPTO’s 2019 Revised Patent
Subject Matter Eligibility Guidance (“Guidance”).7 Under the Guidance, in
determining what concept the claim is “directed to,” we first look to whether
the claim recites:
(1) any judicial exceptions, including “[l]aws of nature,
natural phenomena, and abstract ideas,” (quoting Alice, 573
U.S. at 216) and/or including certain groupings of abstract ideas
(i.e., mathematical concepts, certain methods of organizing
human activity such as a fundamental economic practice, or
mental processes) (Guidance Step 2A, Prong 1); and
(2) additional elements that integrate the judicial
exception into a practical application (see MPEP § 2106.05(a)–
(c), (e)–(h)) (Guidance Step 2A, Prong 2).
Only if a claim (1) recites a judicial exception and (2) does not
integrate that exception into a practical application, do we then look to

7 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg.
50–57 (January 7, 2019).
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whether the claim contains an “‘inventive concept’ sufficient to ‘transform’”
the claimed judicial exception into a patent-eligible application of the
judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82).
In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial
exception that are not “well-understood, routine and
conventional in the field” (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine,
conventional activities previously known to the industry,
specified at a high level of generality, to the judicial exception.
(Guidance Step 2B). See Guidance, 84 Fed. Reg. at 54–56.
Analysis
At the outset, we note that the judicial exception of a “natural
phenomena” identified in the Guidance includes “products of nature.” See
Guidance, 84 Fed. Reg. at 54 n.20 (“This notice does not change the type of
claim limitations that are considered to recite a law of nature or natural
phenomenon. For more information about laws of nature and natural
phenomena, including products of nature, see MPEP 2106.04(b) and (c).”).
As such, claims alleged to be patent-ineligible because they recite products
of nature are properly analyzed under the framework of the Guidance.
Applying the Guidance to the facts on this record, we determine that
Appellant’s claims recite patent-eligible subject matter. Because the same
issues are present in each of the claims, we focus our consideration on
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representative claim 1. The same analysis applied below to claim 1 also
applies to the other rejected claims.
A. Guidance Step 1
We first consider whether the claimed subject matter falls within the
four statutory categories set forth in § 101, namely “[p]rocess, machine,
manufacture, or composition of matter.” Guidance 53–54; see 35 U.S.C.
§ 101. Claim 1 recites a “composition” and, thus, falls squarely within the
“composition of matter” category. Consequently, we proceed to the next
steps of the analysis.
B. Guidance Step 2A, Prong 1
The Guidance instructs us next to determine whether any judicial
exception to patent eligibility is recited in the claim. As noted above, the
Guidance identifies natural phenomena, including products of nature, among
the judicial exceptions to patent eligibility. 84 Fed. Reg. at 54. Under Prong
1 of Guidance Step 2A, we look at individual claim limitations in order to
assess whether the claim recites any such judicial exceptions. Focusing on
the elected species, claim 1 recites a “trimolecular complex” with three
components: (1) a truncated HLA-E heavy chain, (2) beta-2-microglobulin,
and (3) a peptide consisting of SEQ ID NO: 27, and further recites that “the
soluble, truncated HLA-E heavy chain does not contain the transmembrane
and cytoplasmic domains of the native, full length HLA-E heavy chain.”
We understand the claimed complex to require that the peptide of SEQ ID
NO: 27 is loaded onto the antigen binding groove of the soluble HLA-E.
The Examiner, as already noted, finds that the claimed HLA
trimolecular complexes, i.e., a soluble, truncated HLA-E heavy chain, β2m,
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and a peptide (the peptide being loaded into the HLA-E antigen binding
groove (Spec. ¶ 5)), generally, are products of nature (see Final Act. 2–4).
Appellant raises two evidentiary disputes regarding whether the
claimed composition is naturally occurring. First, Appellant contends that
there is “no evidence that Mtb would ever infect endothelial cells to produce
soluble HLA-E molecules having any Mtb related peptides” (Appeal Br. 15).
Second, Appellant contends that “[t]here is no evidence that the claimed
composition has ever been made in nature, nor does it appear likely to ever
actually occur in nature based on a careful reading of the cited references”
(Reply Br. 4).
To resolve these two evidentiary disputes we first turn to the
Specification. The Specification teaches that “HLA molecules isolated from
cell lysates of pathogen-infected cells are . . . currently used to identify class
I HLA-presented peptides.” (Spec. ¶ 9.) The Specification also teaches that
“all people in the population tend to have the same HLA-E on the surface of
all of their cells” and that “HLA-E is thought to act like a classical class I
HLA by presenting M.tuberculosis-derived peptide ligands to T-cells.” (Id.
¶ 8.)
The Specification further teaches that because the “HLA-E-presented
Mtb peptides were purified and identified directly from infected cells, the
presently disclosed and/or claimed inventive concept(s) has directly
established that these HLA-E/Mtb complexes can be used as biomarkers of
an infected cell” (Id. ¶ 25). The Specification also states that “soluble HLA
molecules that enable direct comparative discovery of infected ligands do
not exist in nature -- these soluble HLA have been created in the laboratory.
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Therefore, the soluble HLA/ligand complexes distinct to Mtb-infected cells
disclosed and/or claimed herein do not exist in nature” (id.).
We have also considered the prior art of record. Ravindranath teaches
the existence of soluble HLA-E complexes with antigens in nature, where
Ravindranath states “HLA-E (low polymorphic and highly conserved non-
classical HLA class 1b molecules) is ubiquitously transcribed in all human
tissues . . . over expressed and shed into circulation upon inflammation”
(Ravindranath 423, col. 1). Additionally, Coupel teaches that “HLA-E
forms a heterodimer with β2-microglobulin, which binds and presents
peptides derived from self- or foreign proteins after infection” (Coupel 2806,
col. 1–2). Coupel also teaches “our experiments using inhibitors of
metalloproteinase suggest that HLA-E undergoes proteolysis after reaching
the EC surface. Release of a secreted form of HLA-E resulting from
alternative gene splicing is also supported by our data” (Couple 2813, col.
1).
In the Reply Brief, Appellant asserts that Hernández-Pando8 (first
cited by the Examiner in the Answer) “teaches that stimulation by
inflammatory cytokine TNF-α would be toxic to the endothelial cell [and]
therefore is not likely to lead to soluble release of HLA-E as argued by the
Examiner” (Reply Br. 3). However, Hernández-Pando provides no
discussion of HLA-E or whether HLA-E is released by TNF-α or other
factors, but rather simply states that in tuberculosis lesions “non-professional
phagocytes that take up M tuberculosis in vitro become exquisitely sensitive

8 Hernández-Pando et al., Persistence of DNA from Mycobacterium
tuberculosis in superficially normal lung tissue during latent infection, 356
Lancet 2133–7 (2000).
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to the toxic effects of tumour necrosis factor α” (Hernández-Pando 2137,
col. 1). Thus, Hernández-Pando does not support Appellant’s position
regarding HLA-E release.
However, Hernández-Pando also provides evidence of differential
gene expression by Mtb, differentiating between active Mtb infection and
latent (“quiescent”) turberculosis that occurs “after an immune response has
been generated to control the pathogen and force it into a quiescent state”
(Hernández-Pando 2135, col. 2). In order for Mtb to operate differently in
these different environments, some genes are expressed by Mtb cells causing
an active disease while other genes are expressed by Mtb cells that have
been forced into a quiescent state. Hernández-Pando also points out
differences between Mtb activity during infection in a human patient and
during infection in an in vitro environment, stating “M tuberculosis, which
readily invades such cells in vitro, has been said to be exclusively
extracellular or within macrophages and macrophage-derived cell types in
vivo” (Hernández-Pando 2137, col. 1).
Therefore, as to Appellant’s first argument regarding whether the
trimolecular complex would be cleaved and made soluble, the evidence in
Ravindranath and Coupel suggest that this does naturally occur during
inflammation, and Hernández-Pando does not address this issue as discussed
above, so the evidence as a whole supports the Examiner’s position.
However, as to Appellant’s second argument regarding the trimolecular
complex including SEQ ID NO: 27, the Examiner provides no evidence
demonstrating that this particular trimolecular complex is a naturally
occurring product that results from an Mtb infection, i.e., outside the in vitro
conditions discussed in the specification.
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“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability.” In
re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). The initial burden of
demonstrating that the trimolecular complex including SEQ ID NO: 27 is
naturally occurring therefore rests upon the Examiner, and only if that
burden is met, does Appellant then have the burden of rebutting the
Examiner’s position.
Here, the evidence of record shows that the trimolecular complex is
composed of two components that are present naturally in the human body—
a soluble, truncated HLA-E heavy chain and β2-microglobulin. See
generally Ravindranath; Coupel. The third component of that complex is
the particular eleven-amino acid peptide of SEQ ID NO: 27, which is a
portion of an 83-amino acid source protein that the specification describes as
a “hypothetical protein” (Spec. 22, Table 1). We focus our analysis under
Prong 1 on whether the claim recites a product of nature when the specific
peptide of SEQ ID NO: 27 is bound to HLA-E as part of the trimolecular
complex.
The Examiner provides no evidence on this record that the
hypothetical protein from which SEQ ID NO: 27 is derived is expressed and
presented as an antigen with the other components of the trimolecular
complex in vivo during the course of a natural infection with Mtb. By
contrast, the Specification teaches that the HLA-E peptide epitopes
(including SEQ ID NO: 27) were only identified through in vitro expression
in a non-naturally occurring system, and that the trimolecular complexes
including such peptides were also created in the laboratory (see Spec. ¶ 25
(“these soluble HLA have been created in the laboratory)), ¶ 52 (the HLA
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was obtained from “well characterized Mtb-infected cell lines” (emphasis
added)).
Hernández-Pando demonstrates that Mtb infection can result in
differential expression even under different in vivo conditions by contrasting
actively infected organisms with quiescent organisms (see Hernández-Pando
2135, col. 2). Hernández-Pando further supports a finding that in vitro
expression is not necessarily the same as in vivo expression by teaching
different activities of Mtb in those respective environments (see Hernández-
Pando 2137, col. 1) (“M tuberculosis, which readily invades such cells in
vitro, has been said to be exclusively extracellular or within macrophages
and macrophage-derived cell types in vivo.”) That is, Mtb invades
fibroblasts, endothelium and human epitheilial cells in vitro, but remains
extracellular in vivo, reasonably due to differential gene expression in these
different environments (id.).
Therefore, all of the evidence currently of record supports the
conclusion that Mtb demonstrates differential expression of proteins in vivo
and in vitro. Even if SEQ ID NO: 27 is presented in Mtb-infected cell lines
under the laboratory conditions described in the Specification, there is no
evidence that the same peptide is presented naturally in any humans (or
other animals) infected with Mtb, or that a trimolecular complex including
SEQ ID NO: 27 otherwise exists in nature.
It may be the case, as asserted by the Examiner, that the peptide of
SEQ ID NO: 27 “is naturally processed (Table 1) in an MTb-infected cell
line” (Ans. 6). However, that alone does not establish that the hypothetical
protein from which the peptide sequence is derived exists naturally in a
human (or other animal) host infected with Mtb in view of the teachings of
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Hernández-Pando showing differential protein expression under different
environmental conditions (see Hernández-Pando 2137, col. 1). Moreover,
even if we could assume that the hypothetical protein is naturally expressed
in certain environments, the Examiner points to no evidence of record
showing that the protein is digested in a cell of the natural host in such a way
as to present the specific peptide sequence of SEQ ID NO: 27 in an HLA-E
antigen binding groove. Accordingly, the Examiner provides no evidence
that the particular peptide of SEQ ID NO: 27 is found in nature, either alone
or as part of a trimolecular complex as claimed.
The foregoing analysis is consistent with the analysis in both
Diamond v. Chakrabarty, 447 U.S. 303 (1980) (“Chakrabarty”) and
Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576
(2013) (“Myriad”). In Chakrabarty, the Supreme Court determined that a
bacteria genetically modified to contain two plasmids providing for
hydrocarbon degradation was a “nonnaturally occurring manufacture or
composition of matter—a product of human ingenuity.” Chakrabarty, 447
U.S. at 309. The Court noted that “the patentee ha[d] produced a new
bacterium with markedly different characteristics from any found in nature
and one having the potential for significant utility,” and this discovery was
not nature’s handiwork, but [the patentee’s] own.” Id. at 310. By contrast,
in Myriad, the Court determined that naturally occurring, but isolated, DNA
fell within the product of nature exception because “Myriad’s claims are
simply not expressed in terms of chemical composition, nor do they rely in
any way on the chemical changes that result from the isolation of a particular
section of DNA.” Myriad, 569 U.S. at 593. The Court in Myriad, however,
also noted that “creation of a cDNA sequence from mRNA results in an
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exons-only molecule that is not naturally occurring.” Id. at 594. Although
the Court recognized that, “[i]n rare instances, a side effect of a viral
infection of a cell can be the random incorporation of fragments of the
resulting cDNA, known as a pseudogene, into the genome,” it nonetheless
concluded that the “possibility that an unusual and rare phenomenon might
randomly create a molecule similar to one created synthetically through
human ingenuity does not render a composition of matter nonpatentable.”
Id., n. 8.
Unlike the claims to the naturally occurring DNA at issue in Myriad,
and more similar to the genetically modified bacteria at issue in
Chakrabarty, claim 1 on appeal here is directed to a product of human
ingenuity insofar as it is expressed specifically in terms of a trimolecular
complex that only resulted from efforts undertaken in the laboratory rather
than anything found in nature, i.e., “an isolated class I HLA trimolecular
complex formed in vitro.” To be sure, we recognize that a synthetic product
created in the laboratory may be otherwise identical to or not markedly
different from one that is found in nature, in which case it may not be patent
eligible. See In re Roslin Inst. (Edinburgh), 750 F.3d 1333, 1339 (Fed. Cir.
2014) (determining that claims directed to cloned animals created in the
laboratory were not patent eligible because there was “nothing in the claims,
or even in the specification, that suggests that the clones are distinct in any
relevant way from the donor animals of which they are copies”). But, in this
case, the Examiner has not shown that the trimolecular complex including
the peptide of SEQ ID NO: 27 is merely a copy of a naturally occurring
product.
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The existence of the particular eleven amino acid peptide of SEQ ID
NO: 27 as part of the trimolecular complex with HLA-E and β2-
microglobulin can be analogized to the unusual and rare phenomenon of a
naturally occurring cDNA sequence that was discussed in Myriad. Just as it
was possible that a cDNA of the BRCA1 gene had previously existed in
nature, it is also possible that the particular eleven amino acids of SEQ ID
NO: 27, out of the 83 amino acids of SEQ ID NO: 42 (see Spec. ¶ 22, Table
1), could have been present in a trimolecular complex in one of the millions
of patients infected with Mtb (see Spec. ¶ 7). But that mere possibility is an
insufficient basis for the Examiner’s prima facie case under § 101.
Consistent with Supreme Court and Federal Circuit precedent, we
determine that the proper test to assess whether a product of nature is patent
eligible requires us to draw a distinction between what is necessarily present
in nature and what is only possibly present in nature. That is, if the evidence
of record shows that the putative natural product is not markedly different
from what is necessarily found in nature, that would support a conclusion
that the claimed invention recites patent-ineligible subject matter under
Guidance Step 2A, Prong 1. On the other hand, if the evidence shows the
product is only a mere possibility in nature, that possibility alone does not
support a conclusion of patent ineligibility.
In Myriad, it was beyond dispute that the human genome necessarily
comprised the BRCA1 DNA, whereas there was only a mere possibility that
the BRCA1 cDNA would have been found in nature. Myriad, 569 U.S. at
594. In the instant case, although an Mtb infection would necessarily induce
an HLA-E immune response in humans, as evidenced by Ravindranath and
Coupel, it is at best merely possible that: a) that the protein encoding SEQ
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ID NO: 27 would have been expressed during a natural infection; b) that this
expressed protein would have been cleaved into the specific peptide
consisting of SEQ ID NO: 27; and c) that this specific peptide would have
been incorporated into a trimolecular complex with HLA-E and β2-
microglobulin for surface cleavage and release. As such, the Examiner has
not demonstrated that the claimed trimolecular complex with SEQ ID
NO: 27 necessarily exists in nature.
We appreciate that the Examiner may sometimes present evidence
tending to show that the claimed product appears identical to a natural
product and, in those cases, it may be reasonable to shift the burden to
Appellant. In the instant case, however, the Examiner lacks any such
evidence that a protein encoding the peptide of SEQ ID NO: 27 is expressed
during the natural course of human infection with Mtb or that the
trimolecular complex containing SEQ ID NO: 27 would be naturally present.
With regard to the “markedly different” analysis, we disagree with the
Examiner’s finding that even if there is no “natural counterpart” to the
claimed trimolecular complex, “the breaking of peptide bonds such that a
full length protein is truncated does not confer a marked structural
difference” (Final Act. 3). The Examiner’s analysis, however, does not
properly address the claimed structure insofar as any differences from a
naturally occurring product is not merely the result of the breaking of
peptide bonds.
First, as discussed above, the Examiner has not established that the
full length 83 amino acid hypothetical protein from which SEQ ID NO: 27 is
derived is necessarily expressed during the course of a natural infection with
Mtb, and thus it cannot be said that the shortened 11 amino acid peptide of
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SEQ ID NO: 27 is merely an isolated component of a larger structure known
to be present in nature, similar to DNA isolated from the human genome.
Cf. Myriad, 569 U.S. at 593 (“Nor are Myriad’s claims saved by the fact that
isolating DNA from the human genome severs chemical bonds and thereby
creates a nonnaturally occurring molecule.”). Second, the claimed
trimolecular complex is not merely the result of cleaving away the
transmembrane and cytoplasmic domains of cell surface bound HLA-E, as
suggested by the Examiner, but instead further requires that the shortened
peptide of SEQ ID NO: 27 form a soluble trimolecular complex with a
truncated HLA-E and β2-microglobulin. As such, the markedly different
characteristics for the claimed invention here is not merely due to the
breaking of chemical bonds, but is rather based on chemical differences
attributable to the use of the peptide of SEQ ID NO: 27 within the
trimolecular complex as a whole. Cf. id. (“Myriad’s claims are simply not
expressed in terms of chemical composition, nor do they rely in any way on
the chemical changes that result from the isolation of a particular section of
DNA.”).
Finally, we do not find that the Federal Circuit’s decision in Roche
Molecular Sys., Inc. v. CEPHEID, 905 F.3d 1363 (Fed. Cir. 2018) with
respect to the primer claims mandates a different result. In Roche, the court
explained that it was “undisputed that the [Mtb] primers before us have the
identical nucleotide sequences as naturally occurring DNA,” and that these
“primers are indistinguishable from their corresponding nucleotide
sequences on the naturally occurring MTB rpoB gene.” Id. at 1369. That is,
in Roche, similar to the claimed DNA at issue in Myriad, the Court found
the primers were necessarily present in the natural genome of Mtb. Id. By
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20
contrast, as explained above, there is no evidence of record here that the
trimolecular complex of claim 1 would have naturally occurred in a human
(or other animal) body.
Accordingly, under Guidance Step 2A, Prong 1, we conclude that the
composition of claim 1 does not recite a product of nature, and thus is not
directed to a patent ineligible judicial exception.
C. Guidance Step 2A, Prong 2; Guidance Step 2B
Based on our analysis under Guidance Step 2A, Prong 1, we conclude
that claim 1 is not directed to a product of nature. “If [a] claim does not
recite a judicial exception, it is not directed a judicial exception,” and “[t]his
concludes the eligibility analysis.” Guidance at 54. Accordingly, we do not
proceed to Step 2A, Prong 2 or Step 2B under the Guidance. Id.

Conclusion of Law
We conclude that claims 1–6 and 11–16 are not directed to patent-
ineligible subject matter.

CONCLUSION
In summary:
Claim(s) Rejected Basis Affirmed Reversed
1–6, 11–16 § 101 1–6, 11–16

REVERSED