DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
NOTE: It is noted that the Examiner called Michael Schiff, Attorney on 03/31/26 to propose amending claims 1, 22 and 26 (see allowable subject matter below) and to cancel claims 4 and 6. The Applicant did not agree to the proposal and thus the following rejections have been made.
Status of the claims
The amendment filed 03/06/26 is acknowledged and has been entered. Claims 1, 4, 6-8, 12, 21-22 and 24 have been amended. Claims 13-15 have been canceled. Claims 2-3, 5, 9-11, 18-19 and 26 were previously canceled. Accordingly, claims 1, 4, 6-8, 12, 16-17, 20-25 and 27-29 are under examination.
Withdrawn Rejections
All rejections of claims not reiterated herein, have been withdrawn.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4, 6-8, 12, 16-17, 20-25 and 27-29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and/or to laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, 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); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
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 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 is not “well-understood, routine, 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.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims are directed to a naturally occurring correlation between the presence of PLIN1 autoantibodies in a subject having autoimmune-related lipodystrophy.
Step 2A, Prong 2
The additional elements of contacting a sample with a peptide having an amino acid sequence that is at least 90% identical to any one of SEQ ID NOS: 2 to 6 and detecting whether there are antibodies in the sample that bind to the peptide does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Also, with respect to the recitation “constitutes evidence that the subject is experiencing or is at risk of developing the autoimmune-related lipodystrophy”. The “constitutes evidence” statement at best articulates the judicial exception, amounting only to a general instruction to apply or use the judicial exception. This could read on mental activity being performed solely in a practitioner’ head, e.g. A mental appreciation of the presence of autoantibodies bound to the peptide being correlated with autoimmune related lipodystrophy. No active method steps are invoked or clearly required; the “constitutes evidence” statement does not include any activity that would constitute a practical application, i.e. steps that apply, rely on or use the natural principle in a manner such that the claims amount to significantly more that the natural principal itself.
With respect to the “administering to the subject an immunosuppressive therapy and/or a peroxisaome proliferator-activated receptor agonist” as recited in claims 22 and 24. Although the claim invokes administering a treatment to the subject the claim as currently recites “detecting whether there are antibodies in the sample that bind to said peptide; and if such antibodies are present” Thus, the claim allows for a scenario wherein antibodies are not detected and thus an embodiment wherein no treatment is administered. Therefore, this scenario does not recite something significantly more than the judicial exception.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Further, the additional elements of the claims are recited with a high level of generality and do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. (the active method steps/limitations recited in addition to the judicial exceptions themselves) and do not add significantly more to the judicial exception(s).
As shown by Corvillo et al (Frontiers Immunology, Vol 9, Article 2142, September 2018, pages 1-13) (submitted in the IDS filed 07/13/23) it is well known routine and conventional in the art to obtain a sample from a subject and to contact the sample with a peptide having an amino acid sequence that is at least 90% identical to any one of SEQ ID NOS: 2 to 6 and detecting whether there are antibodies in the sample that bind to the peptide (e.g. page 4).
It does not appear to be the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1, 4, 6-8, 12, 16-17, 20-25 and 27-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 22 and 24 are directed to contacting the sample with a peptide having an amino acid sequence that is at least 90% identical to any one of SEQ ID NO:s 2 to 6.
Claims 1, 22 and 24 as a whole therefore encompasses a genus of polypeptides and peptides for detecting the presence of antibodies associated with lipodystrophy. Thus, the peptides are defined by reference to a desired functional characteristic, namely the capacity to bind to an antibody associated with lipodystrophy.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Although the recitation “at least 90 % identity” may appear somewhat limited, however, the number of amino acid sequences comprising a deletion, substitution and/or addition of is actually enormous. For example, current SEQ ID NO:2 is 49 amino acid residues in length, and the claimed genus includes changes at any given position in the sequence, there is no disclosure of a minimum sequence/epitope that must be retained in order to achieve binding (e.g. to still bind and detect the presence of “antibodies associated with autoimmune-related lipodystrophy.
Thus, the genera encompassed by the claims are of large size and substantial variability. As a result, the number of species meeting the structural requirements of the claim is exceedingly large and characterized by substantial variability; in that any polypeptide having 90% identity be encompassed. As stated above the number of amino acid sequences comprising a deletion, substitution and/or addition of is actually enormous and also allows a diverse number of amino acids added to, deleted or substituted in any combination. It is not apparent that the identities of all such species could be determined even with the aid of a computer.
Furthermore, only those sequences meeting the structural and functional requirements of the genus are encompassed by the claim. Therefore, the claims encompass all of the sequences meeting the structural requirements that are also able to bind to an autoantibody. In this case, however, it cannot be envisioned based on the specification what sequences would possess such binding properties.
Comparing the claim scope with the scope of the description, it is noted that the specification as filed discloses on page 4 discloses polypeptides comprising SEQ IS NO.’s 1-6. Page 37 discloses 5 fragments which have the unique capability of binding to PLIN1 autoantibodies associated with lipodystropy. As shown in Table 1 these fragments are fragments 1-2, 11 and 4-5 which consist of SEQ ID NO.’s 2-6. Thus, the specification is disclosing that fragments 3 and 6-10 did not possess this unique capability. Thus, the specification appears to disclose the full length PLIN1 and 5 very specific amino acid sequences which consist of SEQ ID’s 2-6 having the unique capability of specifically binding to PLIN1 autoantibodies. The, the only examples in the specification which provide the unique characteristic of binding to the PLIN1 autoantibodies consist of SEQ ID NO.’s 1-6.
It was known in the prior art that small changes in antigen structure profoundly affect antibody-antigen interactions. Harlow & Lane (Harlow, E. and Lane, D., Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pages 23-26) discuss how even small changes in antigen structure can profoundly affect the strength of an antibody-antigen interaction. See entire selection, in particular page 26, first full paragraph. In particular, the loss of a single hydrogen bond can reduce the strength of interaction by 1000-fold (ibid).
Many other researchers have reported similar findings to those of Harlow & Lane. For example, Lederman et al. ("A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4" Mol Immunol. 1991 Nov;28(11):1171-81) found that a single amino acid substitution on the antigen CD4 ablated binding of a monoclonal antibody (see title and abstract). Similarly, Colman et al. (Research in Immunology, 1994; 145(1): 33-36) teach that amino acid changes in an antigen can effectively abolish antibody antigen binding entirely (see entire document, particularly pages 33-34).
As noted above, the variability among the peptides encompassed by the claims is also enormous; and would encompass changes much more substantial than the loss of a single hydrogen bond or the mutation of a single amino acid; yet even such minor changes as these were known to dramatically affect function.
Given the unpredictability associated with making even minor changes to antigen structure while preserving function, with limited exception it is not possible to predict which, out of the enormous number of peptides encompassed by the claims, would be capable of binding to an immunoglobulin and/or an immunoglobulin complex.
For all of these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 6, 8, 12, 16-17 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Corvillo et al (Frontiers in Immunology, Vol 9, Article 2142, Sept. 2018, pages 1-13) (submitted in the IDS filed 07/13/23).
Corvillo et al discloses detecting autoimmune-related acquired generalized liposystrophy comprising collecting serum or plasma samples from a subject (e.g. pg 2) and contacting the sample with a recombinant PLIN1 and detecting binding of autoantibodies to the recombinant PLIN1) (e.g. pg 4). Corvillo et al discloses the detection is by ELISA (e.g. pg 4). Corvillo et al discloses that the subject can have an autoimmune disease such as dermatomyositis (e.g. page 1). Corvillo et al discloses that patients with detecting autoimmune-related acquired generalized liposystrophy show the presence of the autoantibodies (e.g. abstract, pgs 6-8). Corvillo et al discloses the subject can show fat loss (e.g. page 2) (early sign of lipodyatrophy).
With respect the recitation “a peptide having an amino acid sequence that is at least 90% identical to any ne of SEQ ID NOS: 2 to 6”. The instantly recited claim is not limited to the recited sequences but utilizes open language in reciting “having an amino acid sequence…” Thus, given its broadest reasonable interpretation any peptide or protein comprising the SEQ ID NO: 2 to 6 would have this peptide and would be 90% identical. Corvillo et al teaches the antigen can be recombinant PLIN1 (OriGene). As evidenced by OriGene product datasheet for TP306292L (pages 1-2, obtained 04/16/2025). the recombinant protein is a human recombinant protein which comprises SEQ ID NO: 3 which begins at the 49th amino acid discloses on the first page of the datasheet. Also, SEQ ID NO: 1 comprises SEQ ID: NO’s 2-6 and therefore it is deemed that the recombinant PLIN1 in the modified method of Corvillo et al reads on the open language of “comprising” and “having an” and comprises an amino acid that is 90% identical to the recited SEQ NO’s. Thus, for the reasons stated above Corvillo reads on the instantly recited claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 7 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Corvillo et al in view of Jehl et al (Diabetes Care, Vol 42, October 2019, pages 2008-2010).
See above for the teachings of Corvillo et al.
Corvillo et al differs from the instant invention in failing to teach the subject has history of treatment with an immune checkpoint inhibitor therapy.
Jehl et al teaches that it is known and conventional in the art that patients receiving nivolumab (checkpoint inhibitor) is associated with acquired generalized lipodystrophy (e.g. abstract, pgs 2008, 2010). Jehl et al discloses the subject has cancer and insulin resistance (e.g. page 1)
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate subjects that have been treated with a checkpoint inhibitor such as taught by Jehl et al because Jehl et al shows that patients receiving a checkpoint inhibitor have a correlation with generalized lipodystrophy. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating subject receiving a checkpoint inhibitor such as taught by Jehl into the method of Corvillo et al.
Claims 22-25 are 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Corvillo et al in view of Bolan et al (The Journal of Clinical Endocrinology & Metabolism, 87 (1), pages 380-384, 2002).
See above for the teachings of Corvillo et al.
Corvillo et al differs from the instant invention in failing to teach administering an immunosuppressive therapy to the subject.
Bolan et al teaches that it is known and conventional to administer plasma exchange (immunosuppressive therapy) to subjects having acquired generalized lipoatrophy (lipodystrophy) and teaches that provides for dramatic improvement in the subject (e.g. abstract, pgs 382-384).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate plasma exchange therapy such as taught by Bolan et al for the subject in the modified method of Corvillo et al because Bolan et al shows that it is known and conventional in the art and provides for dramatic improvement of the subject. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating plasma exchange therapy such as taught by Bolan et al for the subject in the modified method of Corvillo et al.
Response to Arguments
Applicant's arguments filed 03/06/26 have been fully considered but they are not persuasive.
112 (a) written description:
Applicant argues that the question is not whether all of the peptides falling withing the claimed range bind a single isolated PLIN1 antibody. The peptides are not required to have any protein function on their own. The only requirement is that peptides falling within the claimed range be antigenically similar to one of SEQ ID NOS: 2 to 6 to extent that at least some of the PLIN1 specific antibodies in a sample would bind such peptides and thereby be detected.
This argument is not found persuasive because the Applicant is claiming a peptide tied to a function of binding to antibodies associated with autoimmune-related lipodystrophy and the peptide must have a specific structure which provides for the specific function of binding to antibodies that are associated with autoimmune-related lipodystrophy.
Applicant further argues that by way of illustration, suppose the user were to practice the claimed method to test for antibodies in a patient's sample that are specific for SEQ. ID NO:2. The antibodies, if present, will necessarily be polyclonal. As a consequence, the sample will contain different antibody molecules with different antigen combining site that recognize SEQ ID NO:2 in different ways. As a consequence, when the sample is contacted with the SEQ. ID NO:2 peptide in step (b) of claim 1, some antibodies specific for SEQ ID NO:2 in the sample might bind to a particular epitope on SEQ. ID NO:2, others might bind to another epitope. Even for those binding it the same cpitope, because the antibody molecules are polyclonal, at least some will be tolerant to amino acid variations within the contact site. If a variant of SEQ. ID NO:2 is used instead of SEQ. ID NO:2 in step (b), the peptide would be expected capture some but not all of the antibodies against SEQ. ID NO:2 in the sample. This does not affect the accuracy of the determination, because the specific antibodies that are captured in step (b) will be detected in step (c), and thereby give a positive result to the test. Within this degree of tolerance, there are several reasons why SEQ. ID NO:2 is representative of test peptides within the 90% range. First, the antigen combining cleft on an antibody molecule can accommodate at most 9 amino acids of a peptide antigen. Kabat, E.A. Antigenic determinants and the size of the antibody combining site Chapter 6 of Structural Concepts in Immunology and Immunochemistry, 2nd Ed, E.A. Kabat, Holt, Rinehart and Winston, 1976. For a peptide that is 49 amino acids long (such as SEQ. ID NO:2), at least 40 amino acids would necessarily be outside the cleft. Substitutions within the 40 amino acids outside the cleft will usually not affect the ability of the other 9 amino acids to bind to the cleft of the target antibody.
Second, more than 90% of the clinically important epitopes recognized by antibodies are conformational in nature. Barlow D.J. et al. Continuous and discontinuous protein antigenic determinants. Nature, 322, 747-748, 1986. Most peptides that are 90% identical to SEQ ID NO:2 will fold in three dimensional space in the same manner as the prototype - and thereby react with most PLIN1 specific antibodies in the same way.
These arguments are not found persuasive because the written description is not about the antibodies but rather to the peptides themselves. The peptides in the claim are an essential part of the method in that it allows one practicing the method to ascertain whether the antibodies are present. Thus, the issue is whether the Applicant has described the peptide in such terms as to convey to one skill in the art that the inventors had in their possession the broad genus of peptides in the claims at the time the application was filed.
The specification gives only 6 very specific amine acid sequences SEQ IS NO.’s 1-6. Page 37 discloses 5 fragments which have the unique capability of binding to PLIN1 autoantibodies associated with lipodystropy. As shown in Table 1 these fragments are fragments 1-2, 11 and 4-5 which consist of SEQ ID NO.’s 2-6. The specification does not provide a single example of a peptide that is 90% identical to SEQ ID NOS: 2 to 6 or disclosure of a minimum sequence/epitope that must be retained in order to achieve binding (e.g. to still bind and detect the presence of “antibodies associated with autoimmune-related lipodystrophy). Thus, the specification appears to disclose the full length PLIN1 and 5 very specific amino acid sequences which consist of SEQ ID’s 2-6 having the unique capability of binding antibodies associated with autoimmune-related lipodystrophy. The Applicant has not pointed to any disclosure of any structural features common to members of the genus in regard to being able to function to bind the antibodies. Therefore, Applicant has not provided a sufficient description of the genus such that one skilled in the art can visualize or recognize the members of the genus. Also, as stated supra it is not apparent that the identities of all such species could be determined even with the aid of a computer. By way of Applicants on disclosure above not all peptides will bind to the antibodies.
NOTE: It is noted that the Applicant did not provide copies of the Kabat and Barlow references relied upon above.
Applicant’s remaining arguments have been considered but are moot in view of the new grounds of rejection.
Allowable Subject Matter
Claims 1, 22 and 24 would be considered allowable if the Applicant were to amend the step of contacting the sample with a peptide consisting of any one of SEQ ID NOS: 2 to 6. The prior art of record does not teach nor suggest methods as claimed wherein the contacting the sample is with a peptide consisting of any one of SEQ ID NOS: 2 to 6. This step would also provide more than just a judicial exception and would thus be patent eligible.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY W COUNTS whose telephone number is (571)272-0817. The examiner can normally be reached M-F 7:00-4:00.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678
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