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 .
DETAILED ACTION
Applicant’s response filed on 08/06/2026 is duly acknowledged.
Claims 2-4 and 7-11 have been canceled by applicants.
Claims 1, 5, 6 and 12-17, as currently amended/presented are pending in this application.
Claims 13-17 (non-elected Group II, without traverse) remain withdrawn.
Claims 1, 5, 6 and 12 (elected invention of Group I; directed to “A neuroprotective polypeptide compound…”, and “A medicament…”), as currently amended/presented have been examined on their merits in this action hereinafter.
Priority
This application is a 371 of PCT/CN2022/109048 (filed on 07/29/2022), which claims foreign priority from a Chinese application CN 202110873573.5 filed on 07/30/2021.
Objection to Specification & Claims - Withdrawn
In view of amendments to specification as submitted by applicants on 08/06/2026 (related to sequence compliance issue), the objections as previously made by the examiner, has been withdrawn.
Claim Objections - Withdrawn
In view of current amendments to claims 1, 5, 6 and 12, the claim objections as previously made by the examiner have been withdrawn.
NOTE: 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.
Claim Rejections - 35 USC § 103- Made/Maintained
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.
Claims 1, 5, 6 and 12 (as currently amended) are/remain rejected under 35 U.S.C. 103 as being unpatentable over Tymianski (WO 2013/088382 A1; previously made of record) taken with Zhang et al (2018; NPL cited in IDS dated 07/15/2025).
Claim 1 (as currently amended) has been reproduced as follows;
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See also limitations of dependent claims 5, 6 and 12, as currently amended.
Tymianski (2013), while teaching a method of treating the damaging effect of subarachnoid hemorrhage in the subject by administering a peptide drug composition that inhibits the binding of PSD-95 to the NMDAR2 subunit to a subject having subarachnoid hemorrhage (see Tymianski, [0021], [0061], [0079], and Claims 1-52, for instance), discloses (regarding instant claims 1, 5 and 6) a polypeptide comprising amino acid sequence of KLSSIESDV or KLSSIETDV (see Claims 38-42, 49-50; paragraph [0021]; also designated as SEQ ID NOs: 5 and 6, respectively in paragraph [0061] on p. 16, for instance), which corresponds to the CORE amino acid sequence of the polypeptides recited in instant claim 1, 5 and 6 (except for the carnosine residue conjugated on either side of the polypeptide; L-Carnosine being an antioxidant dipeptide, beta-alanine-histidine; see instant specification, p.2, 2nd paragraph); and wherein Tymianski discloses pharmaceutical compositions comprising said polypeptides in pyrogen-free form, and in combination with pharmaceutically acceptable diluents (such as normal saline) or/and carriers, excipients or auxiliaries as per the chosen route of administration (see p. 37, [0117]-[0118], for instance). Tymianski also discloses suitable derivatization of the peptide agents, for example at the N-terminal ends (such as lipidation, or myristoylation; see claim 41, for instance) in order to increase hydrophobicity and facilitate their passage through cell membranes or/and brain barrier (see p. 22-23, [0078], for instance).
However, the polypeptide(s) having amino acid sequences conjugated on either side to beta-alanine-histidine (i.e. carnosine; see instant claims 1, 5 and 6) have not been specifically disclosed by Tymianski, as discussed above.
Zhang et al (2018) disclose conjugation of therapeutic peptides to an strong antioxidant dipeptide such as carnosine for the treatment of CNS disorders, albeit carnosine conjugated to another bioactive polypeptide (see Zhang et al, Title, Abstract on p. 2689, for instance), wherein such derivatization at the N-terminus of the peptide significantly helps in reducing aggregation of beta-amyloid protein and metal-mediated toxicity that are known factors affecting aggravating neurodegenerative processes. Zhang et al disclose the fact that such conjugates significantly reduce the reactive oxygen species (ROS) generation (see “Conclusions” on p. 2697, for instance), which are known and directly linked to oxidative stress and neuronal cell damage (see Introduction on p. 2689, left column 1st paragraph; and p. 2696, section “Effect on ROS Production”, for instance).
Thus, given the disclosure from Zhang et al for the superior anti-oxidant properties of carnosine conjugated peptides agents, to an artisan of ordinary skill in the art in CNS therapy, it would have been obvious to prepare conjugated carnosine peptides at either ends of the therapeutic polypeptides disclosed by Tymianski, as already suggested and demonstrated, for at least the motivation of obtaining superior antioxidant properties of such conjugated peptide derivatives for use in CNS disorder treatments, as disclosed and/or suggested by Zhang et al, as discussed above. Since, the peptide derivatization methods were already known in the art, as also disclosed by Tymianski (such as lipidation of the N-terminal portion of the peptides, in order to increase internalization across a cell membrane or the blood-brain barrier, for instance, see Tymianski, p. 5, [0018], [0072], [0078]-[0079]), given the disclosure from Zhang et al for carnosine conjugates as being superior for their antioxidant properties, an artisan would have been motivated and reasonably successful in preparing such conjugates for the benefits as suggested by Zhang et al, unless evidence/data provided on record to the contrary for the entire scope of the invention as claimed (see instant claim 1, in particular).
In addition, regarding the methyl substitution at histidine residue (see peptides recited with beta-Ala-(1-methyl-His) in instant claim 1), it is to be noted that the issue of patentability over the replacement of alkyl groups for hydrogen has arisen many times. For instance, the replacement of a methylene group with a dialkyl-substituted methylene group was determined to be prima facie obvious on the ground that "one skilled in the art would have been, prima facie, motivated to make the claimed compounds in the expectation that they, too, would possess antimicrobial activity." (In re Wood 199 USPQ 137) See also In re Doebel 174 USPQ 158 (where replacement of methyl for hydrogen on an amino nitrogen was considered prima facie obvious - at page 159); In re Druey 138 USPQ 39 (where replacement of methyl for hydrogen on a known compound was considered prima face obvious based on the homologous and close structural relationship to the known compound - at page 41); In re Lohr 137 USPQ 548 (where the replacement of a methyl group for a hydrogen on two positions of a tetrahydropyran ring on a known compound was not considered a patentable modification given the close structural relationship to the known compounds - at page 550); Ex parte Bluestone 135 USPQ 199 (where fungicidal compounds differing by hydrogen versus methyl on the nitrogen of a thiazolidine-2-thione ring were considered homologs and were not found to be patentable over each other without a showing of unexpected results - at page 200); Ex parte Weston 121 USPQ 429 (where the replacement of methyl for hydrogen on the nitrogen of a piperazine ring was not found to be a patentable modification). The motivation to make a substitution of an alkyl group for hydrogen stems from the fact that a person having ordinary skill in the art would expect that the compounds could be prepared by the same method as taught by the prior art and have the same utility as the compounds taught by the prior art. MPEP 2144.09 (VII) states "A prima facie case of obviousness based on structural similarity is rebuttable by proof that the claimed compounds possess unexpectedly advantageous or superior properties. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)."
The scope of the instant product as claimed (polypeptides or a salt thereof) would have been therefore obvious and fully contemplated by an artisan of ordinary skill in the art given the combined teachings and/or suggestions from the cited prior art references of Tymianski and Zhang et al, as discussed above.
Thus, the claim as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention as claimed.
As per MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. In re American Academy of Science Tech Center, F.3d, 2004 WL 1067528 (Fed. Cir. May 13, 2004)(The USPTO uses a different standard for construing claims than that used by district courts; during examination the USPTO must give claims their broadest reasonable interpretation.). This means that the words of the claim must be given their plain meaning unless applicant has provided a clear definition in the specification. In re Zletz, 893 F.2d 319, 321, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989).
Examiner’s Response to Applicant’s Arguments
Applicant's arguments filed on 08/06/2026 (see REM, regarding the 103(a) rejection of record, p. 7-9) have been fully considered but they are not persuasive for at least the following reasons of record:
First, it is to be noted that, while justifying that all six polypeptides recited in instant claim 1 (i.e. with SEQ ID NOs: 11, 19, 27,35,59 and 60) share the same common core sequence/structure and would be reasonably expected by an artisan of ordinary skill in the art to have similar functional properties (see REM, p. 7, 2-3 paragraph), applicants appear to provide support for the common structural-functional aspects that would have been expected by an artisan of ordinary skill in the art. However, regarding the 103(a) rejection of record over the cited prior art references of Tymianski when taken with Zhang et al, applicants appear to state that “carnosine conjugation is not a routine modification in the field” (see REM, p. 8 1st paragraph) as the specific biological activity and technical effects of the carnosine conjugated peptides as shown by applicants on record, could not be predicted, and are therefore “unpredictable and non-obvious over Tymianski and/or Zhang et al”. Applicants argument is duly noted and considered, but is not deemed persuasive because such statement is not accompanies by any relevant evidence and/or data (for any specific conjugation technique per se that provides any structural difference(s)) on record, and secondly, an artisan in the art would have been motivated to make such modification in the peptide disclosed by Tymianski at least for the benefit of incorporating a superior antioxidant function to the peptide with carnosine that has known function of reducing ROS in neuronal cells, useful for treating CNS-related disorders (see teachings of Zhang et al, and benefits of carnosine conjugates, as discussed above).
The argument that “Zhang et al is directed to an entirely different therapeutic target and mechanism than the present application…” is also not found to be persuasive because such modification would have been obvious and/or fully contemplated by an artisan of ordinary skill in the art, albeit for a different reason than the one argued by the applicants on record. As noted in the rejection of record, it is re-iterated that - since the peptide derivatization methods were already known in the art, as also disclosed by Tymianski (such as lipidation of the N-terminal portion of the peptides, in order to increase internalization across a cell membrane or the blood-brain barrier, for instance, see Tymianski, p. 5, [0018], [0072], [0078]-[0079]), given the disclosure from Zhang et al for the carnosine conjugates as being superior for its antioxidant properties, an artisan of ordinary skill in the art would have been reasonably successful in preparing such conjugates for the known (i.e. ROS reduction in neuronal cells) benefits as suggested by Zhang et al, unless evidence/data provided on record to the contrary.
In addition, applicants appear to argue the non-obviousness based on “unexpected results (such as the ability to penetrate the blood brain barrier)” when administered via intravenous route (see REM, p. 8 last full paragraph and p. 9), which is duly noted and considered. However, as already noted earlier by the examiner, instant claims 1, 5, 6 and 12 under current examination are specifically directed to a product polypeptide and a pharmaceutical composition thereof, and are not specifically drawn to a method of treatment per se. Since, the structural features of the peptides recited in the instant claims when conjugated to carnosine (at either ends, at least for its superior antioxidant properties that were already known in the art), are the same as currently being claimed by applicants, such combination and/or their associated intrinsic functional features (when used in a subject in need) would have been obvious and/or fully contemplated by an artisan of ordinary skill in the art of treating CNS disorders, and therefore does not necessarily render the product unobvious. It is also noted that Zhang et al disclose the fact about the water-soluble dipeptide, carnosine (b-alanyl-L-histidine, Car) that “Car is commonly present in the muscle and brain tissues of humans at high levels, indicating its high biocompatibility” (see Zhang et al, p. 2689, 2nd full paragraph, and cited references therein), and therefore, the arguments based on the non-obviousness for such modification of peptides as currently claimed, are duly noted and considered, but are not found to be persuasive. Also, as per MPEP 2144(IV), The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below).
Thus, the 103(a) rejection of record is properly made and/or maintained.
Conclusion
NO claims are currently 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 SATYENDRA K. SINGH whose telephone number is (571)272-8790. The examiner can normally be reached M-F 8:00- 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE W HUMPHREY can be reached at 571-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SATYENDRA K. SINGH
Primary Examiner
Art Unit 1657
/SATYENDRA K SINGH/Primary Examiner, Art Unit 1657
