DETAILED ACTION
Examiner acknowledges receipt of the reply filed 10/10/2025, in response to the restriction requirement mailed 08/20/2025.
Claims 1, 2, 4-9 and 11-15 are pending. Claim 3 has been cancelled. Claims 7, 8, 11, and 13-15 are withdrawn from further consideration for the reasons set forth herein.
Claims 1, 2, 4-6, 9, and 12 are being examined on the merits in this office 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 .
Election/Restrictions
Applicant's election of Group I (claims 1, 2, 4-9, and 12) with traverse in the reply filed on 10/10/2025 is acknowledged. The traversal is on the ground(s) that “it would not be unduly burdensome to perform a search on all of the claimed together in the present application” (reply filed 10/10/2025). Applicant asserts that “it is known that the NMDA receptor function is regulated indirectly by GPCR stimulation”. Id. Applicant further asserts that that “the antagonists of the present invention rely on direct binding to the NDMA receptor and thereby, N-oleoyldopamine as used by the DiMarchi cannot be considered an NMDAR antagonist in the context of the present invention”. Id.
This is not found persuasive for the following reasons.
Regarding the cited reference DiMarchi, N-oleoyldopamine, is construed as having activity at the NMDA receptor (paras. [0123], [0170]). Examiner notes that claims must be given the broadest reasonable claim interpretation.
The specification states at page 17: The term “NMDAR antagonist” as used herein means a compound which is an antagonist of the NMDA receptor (NMDAR). Contrary to applicant’s assertions, the specification is not limited to direct or indirect activity of the NMDAR. Accordingly, the technical feature of the claimed conjugated molecule was known in the art, and is not considered as a special technical feature.
Examiner further notes that the restriction stated at basis for lack of unity at page 7 of the restriction requirement. Applicant did not address this part of the restriction.
The restriction requirement properly established lack of unity under PCT restriction guidelines. Restriction is made based on the claims as-filed, not based on amended claims filed in reply to the restriction.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11 and 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/10/2025.
Applicant's election of the following representative species with traverse in the reply filed on 10/10/2025 is acknowledged.
Fully defined conjugated molecule: SEQ ID NO:1 directly linked to memantine (no linker)
NMDAR antagonist: memantine
Presence/absence of linker or spacer: absent
Representative species disclosed in Example 1, Fig. 4.
Claims 1, 2, 4-6, 9, and 12 read on the elected species.
Claims 7 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/10/2025.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
The abstract is objected to.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure relates,” etc. In addition, the abstract should be amended to recite separate sentences. The current abstract is one long run-on sentence.
Sequence Interpretation/Claim Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising an amino acid sequence of SEQ ID NO: 1” requires only a dipeptide or more within SEQ ID NO: 1, “comprising the amino acid sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with or without additional amino acids at any N-/C-terminal ends or additional nucleotides at 5' /3' ends, “consisting of an amino acid sequence of SEQ ID NO: 1” would encompass any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, and “consisting of the amino acid sequence of SEQ ID NO: 1” would be limited to the sequence of the amino acids as specified by SEQ ID NO: 1, and nothing more or less; "an amino acid selected from the group consisting of SEQ ID NOs: 1, 2 and 3” is any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, 2 or 3; and “the amino acid selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3.
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.
Claims 1, 2, 4-6, 9, and 12 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient” (MPEP § 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP § 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
In the instant case, the claims recite a conjugated molecule comprising a peptide having at least 80% amino acid sequence identity to SEQ ID NO: 1, 8 or 9, and an N-methyl-D-aspartate receptor (NMDAR) antagonist, the peptide being covalently bonded to the NMDAR antagonist either directly or through a chemical linker. Claim 4 recites wherein the peptide has at least 80% amino acid sequence identity to SEQ ID NO:1. Claim 5 recites wherein the peptide consists of at least 10 amino acids and no more than 60 amino acids. Claim 9 recites wherein the NMDAR antagonist is MK801, neramexane, memantine, memantine hydrochloride, amantadine, ketamine, phencyclidine (PCP), or norketamin.
The specification states “NMDAR antagonist” as used herein means a compound which is an antagonist of the NMDA receptor (NMDAR). Examples of NMDAR antagonist include, but are not limited to, memantine, memantine hydrochloride, amantadine, ketamine or MK801. Further examples of NMDAR antagonist include, but are not limited to, norketamin and neramexane (p. 17, ll. 1-5).
The issue at question is whether a person of ordinary skilled in the art would be able to determine what structural feature/amino acid sequence is required for the instant claimed peptide sequence to be considered to have at least 80% identity to a SEQ ID NO:1, 8, or 9, and to have the functional characteristics of GLP-1. This is further complicated by the identity of “NMDAR antagonists” and liners that can be conjugated to the claimed peptide to yield the claimed conjugated molecules.
(a) actual reduction to practice and (b) disclosure of drawings or structural chemical formulas:
Example 1 discloses preparation of peptides and peptide-NMDAR antagonist conjugates. Conjugates reduce to practice include SEQ ID NO:1-memantine (no linker), penicillamine linked (Pen40/memantine), SEQ ID NO:1-MK801 (cysteine linked, Cys40/MK801), homocysteine linked (Cys40/MK801), or penicillamine linked (Pen40/ MK801) (pp. 28-29).
Thus, only SEQ ID NO:1 [full-length 100% identity] was reduced to practice. Only two NMDAR antagonists were reduced to practice: memantine and MK801. Linkers reduced to practice included penicillamine, cysteine, and homocysteine at amino acid position 40 of SEQ ID NO:1.
Example 2 discloses in vitro human plasma stability assays. Example 3 discloses in vivo pharmaceutical studies in diet -induced obesity mouse models. Example 4 discloses sucrose preference in chow-fed mice.
Taken all these together, other than the limited examples, the instant specification does not describe a general correlation between structure and function for the claimed genus of peptide comprising SEQ ID NO: 1, or variants having at least 80% identity thereof, and further having the function of GLP-1. It is further noted that only two NMDAR antagonists were reduced to practice to yield the claimed conjugated molecules.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure:
As discussed above, in the instant case, based on the disclosure of instant specification, other than the limited examples, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed peptide comprising SEQ ID NO: 1, or peptides having at least 80% identity thereof, and further having the function of GLP-1. It is further noted that the instant peptides can include natural and non-natural amino acids.
Additionally, there is no specific requirement as to what constitutes a NMDAR antagonist. Given the broadest reasonable claim interpretation, the claimed NMDAR antagonist can act directly or indirectly on the NMDA receptor. The antagonist can be of any chemical and physical composition (peptide, nucleotides, lipid, saccharide, or any combination thereof. Collins et al (Pain Medicine 11:1726-1742 (2010)- previously cited) is a review article showing some known NMDA antagonists with diverse structures. See Tables 1 and 2.
It is further noted that only three linkers were reduced to practice - penicillamine, cysteine, and homocysteine at amino acid position 40 of SEQ ID NO:1.
The present application is attempting to patent what has not yet been invented and the fact that one of skill in the art can test for the effect used to determine the compounds does not necessarily confer sufficient written description. The claimed conjugated molecules would entail testing limitless potential peptides and combinations of peptides, NMDAR antagonist, and linkers, and one of skill in the art could afterwards still be faced with no hits with the desired functionality.
In addition, it is well known in the peptide/protein art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein’s function. As an example of the unpredictable effects of mutations on protein function, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282- previously cited) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section “CYSTIC FIBROSIS”. Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation ΔF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2nd paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472- previously cited). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. Although the disclosures of Drumm et al and Yampolsky et al are directed to proteins/peptides other than GLP-1 peptides, they illustrate the inherent unpredictability with respect to the biological activity of a given protein/peptide after even minor changes to the primary amino acid sequence.
Therefore, based on the state of art, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed conjugated molecules comprising SEQ ID NO: 1, or at least 80% identity thereof, and further having the function of GLP-1, much less the identity of NMDAR antagonist that can be functionally combined form the claimed conjugated molecules.
(d) representative number of samples:
In the instant case, the genus of instant claimed peptide sequences recited encompasses numerous variants which may include any number of natural and unnatural amino acids. SEQ ID NO: 1 is 40 amino acids in length. A sequence of 80% identity allows for 8 amino acid changes. This equates to 8 amino acids of any amino acid (20 naturally occurring amino acids) which is 420 or 1.15x1018. These numbers are actually significantly higher when one considers that the that amino acid changes further encompasses both naturally and unnaturally occurring amino acids.
Considering the scope of the genus of instant claimed conjugated molecules, the instant specification fails to provide sufficient examples to describe the entire genus of conjugated molecules claimed. The instant specification is limited to full-length SEQ ID NO:1, two NMDAR antagonists, and 3 single amino acid linkers.
Taken all these together, considering the state of the art and the disclosure in instant specification, it is deemed that the instant specification fails to provide adequate written description for the claimed genus of conjugated molecules comprising SEQ ID NO: 1, 8, or 9, or peptides having at least 80% identity thereof, and further having the function of GLP-1, much less combinations of NDMAR antagonists, and chemical linkers; and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 5, 6, and 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DiMarchi et al. (WO 2011/143208)- previously cited).
DiMarchi et al. teach GLP-1 conjugates (e.g., claim 1). The Y moiety can include compounds such as N-oleoyldopamine which has activity at the NMDA receptor (paras. [0123], [0170]). SEQ ID NO: 1618 of DiMarchi has 100% identity with instant SEQ ID NO:8. SEQ ID NOs:1099 and 1109 [X20 is Aib] of DiMarchi have 100% identity with instant SEQ ID NO:9. Accordingly, the limitations of claim 1 are satisfied.
Regarding claim 5, SEQ ID NO: 1618 is 39 amino acids in length. SEQ ID NOs:1099 and 1109 and 40 amino acids in length. Regarding claim 6, the NMDAR antagonist is covalently bonded at the C- terminal region of the peptide (e.g., claim 1- Y moiety). Regarding claim 12, DiMarchi et al. teach pharmaceutical compositions comprising the conjugated molecule and a pharmaceutically acceptable carrier (e.g., paras. [0015], [0020], [0837]-[0844]).
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.
Claims 1, 2, 4, 5, 9, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-36 of copending Application No. 18713092 (hereinafter referred to as “the ‘092 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1, claim 16 of the ‘092 application is drawn to a conjugated molecule comprising a peptide and a N-methyl-D-aspartate receptor (NMDAR) antagonist, wherein the peptide has at least 85% amino acid sequence identity to SEQ ID NO:1 or wherein the peptide is according to SEQ ID NO:1, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8, the peptide being linked to the NMDAR antagonist either directly or through a chemical linker, wherein the NMDAR antagonist is selected from memantine, neramexane, and dizocilpine. SEQ ID NO:1 of the ‘092 application has 100% identity with instant SEQ ID NO:1.
Regarding claim 2, claim 20 of the ‘092 application recites wherein the NMDAR antagonist in its free form has a dissociation constant with an NMDA receptor in the range of about 0.5 nm to 1000 nM.
Regarding claim 4, claim 19 of the ‘092 application recites wherein the peptide has more than 90% identity to SEQ ID NO:1.
Regarding claim 5, SEQ ID NO:1 is 40 amino acids in length.
Regarding claim 9, claim 16 of the ‘092 application recites that the NMDAR antagonist is memantine, neramexane, or dizocilpine.
Regarding claim 12, claims 31-36 of the ‘092 application are drawn to a pharmaceutical composition comprising a conjugated molecule comprising a peptide and a N-methyl-D-aspartate receptor (NMDAR) antagonist, wherein the peptide has at least 85% amino acid sequence identity to SEQ ID NO:1 or wherein the peptide is according to SEQ ID NO:1, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8, the peptide being linked to the NMDAR antagonist either directly or through a chemical linker, wherein the NMDAR antagonist is selected from memantine, neramexane, and dizocilpine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Accordingly, claims 1, 2, 4, 5, 9, and 12 are anticipated by the claims of the ‘092 application.
Relevant Art Not Relied Upon
Peterson et al (Drugs 79:1187-1197, epublished June 29, 2019- cited in IDS filed 11/16/2022; post-filed art) is an article by applicants. Peterson et al teach that poly-agonist pharmacotherapies targeting dissimilar signaling pathways are emerging and demonstrate promising preclinical efficacy (p. 1187). The merging pharmacological concept of peptide-mediated targeting of small molecules for tissue-specific delivery holds promise for more powerful treatment solutions in the future. The reference summarizes recent advances in medicinal chemistry and molecular pharmacology that have enabled the engineering of several, novel, poly-agonist drug candidates for treatment of metabolic diseases, including results from clinical trials assessing the efficacy and safety of glucagon-like peptide (GLP)-1/glucagon and GLP-1/GIP co-agonists (abstract). Figure 3 discloses several sequences for GLP-1 agonists.
Conclusion
No claims are allowed.
Claims 1, 2, 4-9 and 11-15 are pending. Claims 7, 8, 11, and 13-15 are withdrawn from further consideration for the reasons set forth herein.
Claims 1, 2, 4-6, 9, and 12 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654