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 .
Status of Application, Amendments and/or Claims
1. Claims 66-73 have been amended and claims 37, 39-43 and 52-65 have been canceled as requested in the amendment filed June 13, 2025. Following the amendment, claims 66-76 are pending in the present application.
2. Claims 66-76 are under examination in the current office action.
Withdrawn Objections and Rejections
3. Any objection or rejection of record pertaining to any of canceled claims 37, 39-43 or 52-65 is rendered moot by applicant’s amendment.
4. The objections to claims 66-73 for minor informalities are withdrawn in view of applicant’s amendments to the claims.
Maintained Claim Rejections
Claim Rejections - 35 USC § 103
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.
5. Claim(s) 66-76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gygi et al. (US 2006/0148093 A1) in view of Memo et al. (US 2018/0057572 A1), Meek et al. (Cold Spring Harb. Perspect. Biol. 2009, 00:a000950) and DeHart et al. (Mol. Cell Proteomics, 2014, 13(1):1-17) (all references of record). The rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously and therefore will not be reiterated here. See section 10 of the 01/16/2025 office action.
Response to Arguments
6. In the response filed 06/13/2025, applicants argue that the amended claims are not obvious over the combined prior art teachings because: the cited art fails to teach or suggest the claimed invention; there is not an articulated motivation to combine the references in the manner required by the claims; and there is no reasonable expectation of success in achieving the claimed invention based upon the cited art.
In particular, applicants argue that none of Gygi, memo, Meek or DeHart disclose or suggest the detection of particular combinations of PTMs on plasma-derived U-p53 for clinical purposes, as recited in the claims. Applicants assert that simply identifying individual elements across multiple references does not render a claim obvious unless the art provides a reason to combine them in the claimed manner. And here, applicants contend, the different references are directed to fundamentally different objectives.
With respect to an alleged lack of motivation to combine, applicants argue that Gygi provides no motivation to combine with Memo, DeHart or Meek, and that the filed of biomarker diagnostics is biologically complex and the “obvious to try” rationale is inapplicable absent a finite number of predictable solutions.
And regarding an alleged lack of reasonable expectation of success, applicants argue that the combination of prior art references fails to demonstrate that U-p53 PTMs can be reproducibly detected in plasma, or that they correlate reliably with any disease state. According to applicant, the lack of guidance in the prior art would require undue experimentation to identify the PTMs and their correlation with specific neurodegenerative phenotypes, and that only impermissible hindsight knowledge found in the instant application would provide the necessary guidance.
7. Applicants’ arguments have been considered but are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the presently claimed methods recite “comprising” language, and therefore are not limited to the detection of particular combinations of U-p53 PTMs. Rather, the broadest reasonable interpretation of claim 66, for example, encompasses the detection of more than just the specific combination of PTMs that are recited (i.e., “(i) at least two PTMs selected from PTM-1, -3, -4, -5 and -6, -9, -10, and (ii) at least one PTM from PTM-2, -7, -8 and -11”) and thus may include the detection of all of the recited PTMs. Furthermore, diagnosis is not required by the claims, only detection of PTMs is required.
The Meek and DeHart references disclose the PTMs of the present claims, as well as several other p53 PTMs. Given that the Gygi and Memo teach and even claim that PTMs can be detected in plasma, and that the identification of PTMs in p53 can be used in the determination or diagnosis of neurodegenerative disease, such as Alzheimer’s disease (AD), there would have been both motivation to detect multiple p53 PTMs and a reasonable expectation of success in detecting these PTMs as disclosed in the prior art and as instantly claimed. In particular, given the known p53 PTMs taught by Meek and DeHart, and the recognition that PTMs in p53 are associated with neurodegenerative disease, one of ordinary skill in the art would have been motivated to have tried to detect any or all of the p53 PTMs known in the prior art, which would comprise the detection of the instantly recited combinations of PTMs.
Again, the correlation of specific combinations of PTMs to disease for diagnosis is not required by the claims; only detection of PTMs is necessary. Such detection can be performed, as evidenced by Meek and DeHart, using well-known, conventional and routine laboratory techniques (e.g., HPLC-mass spectrometry) which provides a basis for a reasonable expectation for success.
Regardless, KSR forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. Rather, an additional rationale for the instant finding of obviousness is that the claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. For example, it would have been obvious to try to detect and identify the various p53 PTMs in a plasma sample from a subject suspected of having a neurodegenerative disease or cognitive decline, which amounts to choosing from a finite number of identified, predictable solutions (i.e., p53 PTMs known in the prior art) with a reasonable expectation of success. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Finally, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, all elements of the instant claims (i.e., plasma as biological sample, the association between p53 PTMs and neurodegenerative disease, and the different p53 PTMs themselves) were recognized within the prior art references of record, and therefore the detection of multiple of the PTMs would have been obvious. The rejection of claims 66-76 is thus maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
8. Claims 66-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-18 of copending Application No. 17/699,030 (reference application); and
claims 1-11 of copending Application No. 18/007,088 (reference application).
The rejections are maintained for reasons of record and as discussed below.
Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass the detection of the same PTMs within the p53 protein, and determination of the same neurodegenerative disease or cognitive condition in a subject, using the same methodology. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
9. For each of the above rejections, applicants argue that present claims are not obvious over the claims of the co-pending applications, and also that the scope of each of the co-pending applications has not been finalized.
10. Applicants’ arguments have been considered but are not persuasive. As stated above and previously, the claims of the ‘030 and ‘088 applications are directed to the same methods as encompassed by the present claims, and therefore teach or obviate the presently claimed invention. Note that the instant application, the ‘030 application, and the ‘088 application each share the same patent term filing date, and therefore it is proper to maintain the provisional rejections. See MPEP §1490 (VI)(D)(2)(b), which states that when the application under examination and the reference application have the same patent term filing date, the provisional nonstatutory double patenting rejection made in each application should be maintained until it is overcome.
Conclusion
11. No claims are allowed.
12. THIS ACTION IS MADE FINAL. 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.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675