Marios Hadjivassilliou et al.

Patent Trials and Appeals Board

Dec 13, 2019

12594926 - (D) (P.T.A.B. Dec. 13, 2019)

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.
12/594,926 02/08/2010 Marios Hadjivassilliou 6333-00900 8223
35690 7590 12/13/2019
KOWERT, HOOD, MUNYON, RANKIN & GOETZEL, P.C.
P.O. BOX 398
AUSTIN, TX 78767-0398
EXAMINER
DUTT, ADITI
ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
12/13/2019 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):
patent_docketing@intprop.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte MARIOS HADJIVASSILLIOU and DANIEL AESCHLIMANN
____________

Appeal 2018-003640
Application 12/594,926
Technology Center 1600
____________

Before DONALD E. ADAMS, ULRIKE W. JENKS, and JOHN G. NEW,
Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims directed to a method of diagnosing an autoimmune disorder.
Examiner rejected the claims as containing patent ineligible subject matter
and for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a). Appellant identifies the real party in interest as Zedira GmbH.
Appeal Br. 2.
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STATEMENT OF THE CASE
The Specification teaches “transglutaminase gene, TGM6 (SEQ ID
No. 1), which encodes the enzyme transglutaminase 6 / transglutaminase y
(TG6, SEQ ID No. 2) (WO 02/22830 [Aeschlimann]) . . . constitute a
functional transamidase.” Spec. 5:24–26. The Specification explains that
“TG6 is expressed predominantly in the central nervous system in the
developed organism,” and the role of transglutaminase 6 expression during
development is under investigation. Id. at 19:13–14.
Claims 1, 6–8, 16–19, 21–24, and 26–29 are on appeal, and can be
found in the Claims Appendix of the Appeal Brief. Claim 1 is representative
of the claims on appeal, and reads as follows:
1. Method for the diagnosis of an autoimmune disorder
selected from the group consisting of ataxia, ataxia with
myoclonus, encephalitis, epilepsy with occipital cerebral
calcifications, peripheral neuropathy, or loss of sensation, the
method comprising:
providing a sample from a subject suspected of having
the autoimmune disorder;
contacting the sample with immobilized
transglutaminase 6, or an immobilized antigenically active
fragment thereof;
detecting autoantibodies from the sample that react with
transglutaminase 6 or the antigenically active fragment thereof,
and;
comparing the level of the autoantibodies from the
sample that react with transglutaminase 6 or the antigenically
active fragment thereof with a respective level of a reference;
wherein an increase in autoantibodies that react with
transglutaminase 6 or the antigenically active fragment thereof
detected in the sample compared to the level of antibodies in
the reference means that the subject suspected of having the
autoimmune disorder has said autoimmune disease.
Appeal Br. 14 (Claims Appendix).
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Appellant requests review of the following grounds of rejection made
by Examiner:
I. Claims 1, 6–8, 16–19, 21–24, and 26–29 under 35 U.S.C. § 101, as
directed to patent ineligible subject matter.
II. Claims 1, 6, 16–17, 21–22, and 26–27 under 35 U.S.C. § 103(a) as
unpatentable over Aeschlimann2 and Chin.3
III. Claims 1, 6–8, 16–19, 21–24, and 26–29 under 35 U.S.C. § 103(a) as
unpatentable over Aeschlimann, Chin, and Kim.4

I Patent Ineligible Subject Matter
Examiner finds that the claims are directed to patent ineligible subject
matter, namely to a law of nature. Examiner explains that “[t]he claims are
directed to a judicial exception comprising a naturally occurring principle of
transglutaminases (TG) (primarily TG6) antibodies and its implication in
autoimmune disorders characterized by neurological dysfunction, like
peripheral neuropathy, ataxia, etc. as recited in claims 1, 16, 21 and 26.”
Final Act. 3–4. Specifically, Examiner explains that “[t]he use of TG
antigens naturally present in the body for the detection of naturally occurring
antibodies for the diagnosis of autoimmune disorders do not impose
meaningful limits on the claim scope, so that others are not substantially
foreclosed from using the judicial exception(s).” Id. at 4. Examiner
explains that comparing antibody levels and thereby diagnosing the subject

2 Aeschlimann et al., WO 02/22830 A2, published March 21, 2002
(“Aeschlimann”).
3 Chin et al., Celiac neuropathy, 60 Neurology 1581–85 (2003)(“Chin”).
4 Kim et al., Transglutaminases in disease, 40 Neurochemistry International
85–103 (2002)(“Kim”).
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is a mental step, such as for example “checking bands on a gel.” Id. at 4.
Additionally, Examiner points out that the use of antigens for the diagnosis
of autoimmune disorders is known in the art. Id. at 5. Therefore, even when
analyzed as a whole Examiner concludes the claims remain patent ineligible
because the limitations recited in the claims failed to establish that the
claims are not directed to a law of nature/abstract idea. Id. at 6.
Appellant contends “that the methods claimed are the result of human
ingenuity and research and that the claims recite a judicial exception.”
Appeal Br. 6.
Appellant does not argue the claims separately. We analyze claim 1
as representative. We agree with the Examiner’s factual findings and
conclusion that claim 1 is directed to patent ineligible subject matter.
An invention is patent-eligible if it claims a “new and useful process,
machine, manufacture, or composition of matter.” 35 U.S.C. § 101.
However, 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. E.g., Alice Corp. v. CLS Bank Int’l, 573 U.S. 208,
216 (2014).
The Supreme Court has established a two-step framework for
“distinguishing patents that claim laws of nature, natural phenomena, and
abstract ideas from those that claim patent-eligible applications of those
concepts.” Id. at 217. “First, we determine whether the claims at issue are
directed to” a patent-ineligible concept. Id. If so, “we consider the elements
of each claim both individually and ‘as an ordered combination’ to
determine whether the additional elements ‘transform the nature of the
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claim’ into a patent-eligible application.” Id. (quoting Mayo Collaborative
Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 78–79 (2012)).
The United States Patent and Trademark Office (PTO) issued the
2019 Revised Patent Subject Matter Eligibility Guidance (“Guidance”),
indicating how the PTO can analyze patent eligibility under the Supreme
Court’s two-step framework and the October 2019 Update to the Revised
Guidance (“Update”), which provides further details regarding how the
Patent Office is to analyze patent-eligibility questions under 35 U.S.C.
§ 101. 84 Fed. Reg. 50−57 (Jan. 7, 2019); 84 Fed. Reg. 55,942 (Oct. 18,
2019). Applying the Guidance and Update, we agree with the Examiner that
the pending claims are directed to patent ineligible subject matter, namely a
law nature.
STEP 1:
We first find that claim 1 is directed to a “[m]ethod for the diagnosis
of an autoimmune disorder….” We therefore conclude that the claims are
directed to a method or a “process,” and thus falls into one of the broad
categories of patentable subject matter under Section 101.
STEP 2A, Prong One:
Under the Guidance, in determining what concept a claim is “directed
to” in step one of the Supreme Court’s two-step framework, we first look to
whether the claim recites any judicial exceptions to Section 101, such as an
abstract idea, a law of nature, or a natural phenomenon. Guidance, 84 Fed.
Reg. at 52, 54 (Step 2A, Prong One).
In Mayo, the Supreme Court found that a claim was directed to a
natural law, where the claim required administering a drug and determining
the levels of a metabolite following administration, where the level of
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metabolite was indicative of a need to increase or decrease the dosage of the
drug. Mayo, 566 U.S. at 74; Athena Diagnostics, Inc. v. Mayo Collaborative
Servs. LLC, 915 F.3d 743, 750, 753–54 (Fed. Cir. 2019) (noting that
detecting the presence of a label in a method for diagnosing
neurotransmission or developmental disorders related to MuSK comprising
contacting labeled MuSK with a bodily fluid, immunoprecipitating any
antibody/MuSK labeled complex, monitoring for the label, and noting the
presence of the label is indicative of a neurotransmission or developmental
disorder related to MuSK, involves “the correlation between the presence of
naturally-occurring MuSK autoantibodies in bodily fluid and MuSK-related
neurological diseases” that “exists in nature apart from any human action.”).
Claim 1 requires “comparing the level of the autoantibodies from the
sample that react with transglutaminase 6 or the antigenically active
fragment thereof with a respective level of a reference” and in increase in
autoantibodies is indicative of the patient having an autoimmune disorder.
This “comparing” step recites a natural law, i.e., the correlation between the
concentration of certain naturally occurring autoantibodies and the presence
of an autoimmune disorder.
STEP 2A, Prong Two:
Having made the determination that claim 1 recites a natural law,
under the Guidance, we next examine whether there are additional elements
beyond the natural law that integrates the judicial exception into a practical
application. Under the Guidance, this is referred to as the “Prong Two”
inquiry under “Step 2A.” Guidance, 84 Fed. Reg. at 54–55. That is, under
the Prong Two analysis we look to whether the claim as a whole “appl[ies],
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rel[ies] on, or use[s] the judicial exception in a manner that imposes a
meaningful limit on the judicial exception.” Id.
The additional steps here include the data gathering to determine the
levels of autoantibodies in a test sample and compare it to a reference, i.e., a
control. The Specification does not indicate that any particular method of
determining the autoantibody is required; rather it explains that this
determination can be done by immunoassay to assess the presence and
concentration of antibodies to transglutaminase 6. Spec. 23. The
determination of the amount of antibody in a control sample used for the
comparison also does not require the application of a particular method. As
our reviewing court has explained application of “conventional techniques to
detect [the] . . . natural law” are not a particular application of the natural
law. See Athena, 915 F.3d at 751 (the patent “describes the claimed
invention principally as a discovery of a natural law, not as an improvement
in the underlying immunoassay technology.”). Similar to the “determining”
step in Mayo, here the “comparing” step tells the person performing the
method to determine the concentration of autoantibodies through whatever
process that person wishes to use. See Mayo, 566 U.S. at 79. The “wherein”
step simply notes that a particular conclusion can be drawn in light of the
correlation: “rather like Einstein telling linear accelerator operators about
his basic law and then trusting them to use it where relevant.” Id. at 78.
Thus, the claimed diagnostic method is not a practical application of the
natural law.
STEP 2B:
Step 2B requires that we look to whether the claim “adds a specific
limitation beyond the judicial exception that [is] not ‘well-understood,
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routine, conventional’ in the field.” See MPEP § 2106.05(d) (9th ed., rev.
08.2017 (Jan. 2018)). The Examiner found, the detection of antibodies
against transglutaminase 6 comprising a competitive protein binding assay
using transglutaminase 6 antigen or portions thereof, for the diagnosis of
autoimmune disorders is known in the art. Final Act. 5 (citing
Aeschlimann). Thus, the steps of collecting a sample, detecting antibodies
in the sample using a binding assay format, and comparing the results with a
control, when considered individually or as an ordered combination are well-
understood, routine, and conventional.
Based on the foregoing, therefore, we conclude that claim 1 is
directed to a judicial exception without significantly more, and therefore, is
not eligible for patent protection. Claims 6–8, 16–19, 21–24, and 26–29
have not been argued separately and therefore fall with claim 1. 37 C.F.R.
§ 41.37(c)(1)(iv) (2017).
II. Obviousness over Aeschlimann and Chin
Does the preponderance of evidence of record support Examiner’s
conclusion that Aeschlimann and Chin teach a method of diagnosing
autoimmune disease as claimed?
Findings of Fact
We adopt Examiner’s findings concerning the scope and content of
the prior art. For emphasis, we highlight the following:
FF1. Aeschlimann teaches transglutaminase gene TGM6 that encodes
amino acid sequence of TGY. Aeschlimann 4, see Figure 10.
FF2. Aeschlimann teaches TGY expression in cells having characteristics of
neuronal cells.
TGY expression . . . was very restricted and expression
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was only found in H69 cell line. This cell line has
characteristics of neuronal cells such as the expression of
neuron-specific enolase and brain isozyme of creatine
kinase which together with widespread expression in
tissues of the nervous system suggests that TGY
expression may be specific to neuronal cells.
Transglutaminase action has been implicated in the
formation of aberrant protein complexes in the central
nervous system leading to nerve cell degeneration, e.g in
Alzheimers and Huntington’s disease. Based on its
expression pattern, TGY is a logical candidate to bring
about the underlying transglutaminase-related
pathological changes.
Aeschlimann 20.
FF3. Aeschlimann teaches diagnosing autoimmune diseases including
progressive systemic sclerosis and systemic lupus erythematosus
(SLE). Aeschlimann 34 (claim 31).
FF4. Aeschlimann teaches detecting antibodies to transglutaminase 6.
[A] competitive protein binding assay for the differential
diagnosis of autoimmune diseases comprising the
detection of antibodies against the transglutaminase
encoded by the nucleotide sequence [TGM7 and TGM6]
. . . , or portions thereof. Preferably the protein binding
assay comprises using exogenous transglutaminase TGz
or TGy, or both, as a competitive antigen.
Aeschlimann 8 (citing Fig. 6 and 10), see id. at 34 (claims 32–34).
FF5. Chin teaches that “[c]eliac disease (CD) is a chronic inflammatory
enteropathy resulting from sensitivity to ingested gluten. It is
characterized by elevated titers of antibodies to gliadin and
transglutaminase, . . . .” Chin 1581. Chin teaches that
“[a]pproximately 10% of CD patients have an associated neurologic
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disease, most often peripheral neuropathy or ataxia but also seizures,
dementia, or psychiatric illness.” Id.
FF6. Chin teaches measuring IgA transglutaminase antibodies using a
commercially available assay. Id.

Principle of Law
“If the claim extends to what is obvious, it is invalid under § 103.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007).
Where a patentee uses the claim preamble to recite structural
limitations of his claimed invention, the PTO and courts give
effect to that usage. Conversely, where a patentee defines a
structurally complete invention in the claim body and uses the
preamble only to state a purpose or intended use for the
invention, the preamble is not a claim limitation.
Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997) (citations omitted).
Analysis
As Appellant does not argue the claims separately, we select claim 1
as representative and focus our analysis that claim. Claims 6–8, 16–19, 21–
24, and 26–29 stand or fall with claim 1. 37 C.F.R. § 41.37 (c)(1)(iv).
Claim Construction
Claim 1’s preamble indicates that the method recited in the body of
the claim is intended for diagnosing autoimmune disorders, the preamble
attempts to narrow the autoimmune disorder to encompass a list of
symptoms associated with said disorders. Here, the intended use recited in
the preamble of the method is not a claim limitation because the body of the
claim sets out the all the limitations needed to carry out the method,
regardless whether the patient is ultimately found to have an increase in the
level of autoantibodies indicative of an autoimmune disorder. We agree
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with Examiner’s interpretation and find that the body of the claim sets forth
all the limitations of the claimed invention such that the preamble phrase
only states an intended use, i.e., a diagnosis of an autoimmune disorder. See
Rowe, 112 F.3d at 478; see also Ans. 7 (“[T]he claims only require diagnosis
of autoimmune disease.”); Final Act. 10 (“[The] clause at the end of the
claim[s 16, 21, and 26] recites a result of the method or an intended outcome
of the steps, but not a step that is to be performed by the artisan.”).
The body of the claim 1 sets out the steps involved in determining
whether a patient sample contains antibodies reactive with
transglutaminase 6. The steps involved are obtaining a sample, reacting the
sample with transglutaminase 6, and comparing the results to a reference
sample. In this case, there is no change in the way the method is performed
regardless of whether the patient ultimately is found to exhibit higher
antibody levels indicative of autoimmune disease. See Bristol-Myers Squibb
Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1375 (Fed. Cir. 2001) (“The
steps of the . . . method are performed in the same way regardless whether or
not the patient experiences a reduction in hematologic toxicity, and the
language of the claim itself strongly suggests the independence of the
preamble from the body of the claim.”). Accordingly, we find that the
preamble of claim 1 states an intended use but does not otherwise further
limit the claim.
Discussion
Examiner finds that Aeschlimann teaches transglutaminase 6 and
antigenically active fragments, as well as methods for detecting
transglutaminase or autoantibodies against the transglutaminase. Final
Act. 9; Ans. 10; FF1–FF4. Examiner finds that in addition to detecting
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transglutaminase 6 Aeschlimann also teaches the detection of additional
antibodies such as transglutaminase 7. Final Act. 9; FF4. Examiner finds
that all protein binding assays have accepted common process steps,
therefore, Aeschlimann’s competitive protein binding assays meets the claim
limitations set out in claim 1. Final Act. 9; FF4. Examiner finds that
Aeschlimann teaches that transglutaminase 6 is associated with a neuronal
cell type and therefore implies an involvement in neurological pathology.
Final Act. 10; Ans. 10; FF2. Examiner recognizes that Aeschlimann does
not explicitly state diagnosis of ataxia (Final Act. 10), but finds that
Aeschlimann does disclose “progressive systemic sclerosis or SLE [that] are
autoimmune diseases accompanied with ataxia. . . . Even though the claims
recite that the disease is ataxia, it is commonly understood that ataxia is not a
disease by itself, rather is a neurological sign present in different diseases.”
Ans. 7. Examiner relies on Chin for teaching an autoimmune disease that
displays the symptoms of ataxia. Final Act. 11; FF5. According to
Examiner, it would have been obvious to combine Aeschlimann and Chin
because each of the references discloses detecting autoantibodies against the
transglutaminase. Final Act. 11; Ans. 12 (“The fact that TG6 is specifically
present in the neurons, the knowledge that autoimmune diseases are
implicated by TG (both TG6 and TG2) antibodies, and that ataxia is
associated with autoimmune diseases linked to TG antibodies, will motivate
the person of ordinary skill to use different TG antibodies for detection of
said diseases associated with ataxia.”); FF4–FF6.
Appellant acknowledges that “Aeschlimann refers to a link between
autoimmune disease and TG6, [but argues that] none of the 30 or so
autoimmune diseases listed have in fact any overlap with the autoimmune
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disorders claimed.” Appeal Br. 9. Appellant contends that “that
transglutaminase 2 (TG2) and transglutaminase 6 (TG6) are inherently
different proteins and that no generalization can be made from one
transglutaminase protein to the other.” Id. at 8. In addition, autoantibodies
are generally not cross-reactive. Id. Further, “Appellant notes that while
Aeschlimann teaches diagnosis of autoimmune diseases, Aeschlimann fails
to teach autoimmune neurological dysfunction.” Id. at 9. Appellant
contends that Aeschlimann does not address autoantibodies in
neurodegenerative diseases, and ataxia. Id. Appellant contends that Chin’s
analysis is exclusively directed at celiac patients and does not make a
connection to a specific pathogenic mechanism involving autoantibodies.
Id. at 11.
We have reviewed Appellant’s contentions that the Examiner erred in
rejecting claim 1 as obvious over the cited art. We disagree with
Appellant’s contentions. As discussed above (see Claim Construction),
claim 1 is interpreted as being directed to a method of detecting antibodies to
transglutaminase 6.
Aeschlimann teaches transglutaminase 6 and antigenic fragments
thereof. FF1. Aeschlimann also teaches diagnosing autoimmune diseases
by detecting either the protein transglutaminase 6 or detecting autoantibodies
to transglutaminase 6 using competitive protein binding assays. FF2–FF4.
Aeschlimann also teaches detecting multiple transglutaminases, in order to
provide a differential diagnosis. FF4. Thus, Aeschlimann already suggests
assaying a sample for multiple different transglutaminase antibodies.
Chin teaches that celiac disease, is an inflammatory enteropathy that
is characterized by having elevated antibodies against transglutaminase.
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FF5–FF6. Because claim 1 encompasses detecting antibodies to multiple
transglutaminases we agree with Examiner’s conclusion that based on the
disclosures in Aeschlimann and Chin, the references teach a method of
diagnosing an autoimmune disorder as recited in claim 1.
We affirm the rejection of claim 1 under 35 U.S.C. § 103 over
Aeschlimann and Chin. Claims 6, 16−17, 21−22, and 26−27 were not
separately argued and fall with claim 1.

III. Obviousness over Aeschlimann, Chin, and Kim
Appellant contends that Kim does not appear to remedy the
deficiencies of Aeschlimann and Chin. Appeal Br. 12. Having found no
errors with the combination of Aeschlimann and Chin, we are not persuaded
by Appellant’s contention that Kim fails to make up for any alleged
deficiency in the combination. Accordingly, we affirm the rejection of claim
1 for the reasons set out by Examiner in the Final Office Action and Answer.
Claims 6–8, 16–19, 21–24, and 26–29 have not been argued separately and
therefore fall with claim 1.

SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 6–8,
16–19,
21–24,
26–29
101 Patent ineligible
subject matter
1, 6–8, 16–
19, 21–24,
26–29

1, 6,
16−17,
103 Aeschlimann, Chin 1, 6, 16−17,
21−22,
26−27

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21−22,
26−27
1, 6–8,
16–19,
21–24,
26–29
103 Aeschlimann,
Chin, Kim
1, 6–8, 16–
19, 21–24,
26–29

Overall
Outcome
1, 6–8, 16–
19, 21–24,
26–29

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED