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 .
Election/Restrictions
Claim 1 is directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 18, 19, and 21, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 3/21/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 7/21/2021 and 12/01/2022 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The specification was previously objected to on the following grounds:
All peptides of four or more specified residues require a sequence identifier. The same is true for nucleic acids of 10 or more specified residues. See specification page 38, Table 1; page 41, para [00152]; page 41, Table 2; and page 43, Table 6. See also claim 14.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 14, para. 5, filed 4/7/2026, with respect to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Drawings
The drawings were previously objected to under 37 CFR 1.83(a) because they failed to show the features and details as described in the specification at para. [0040], [00163], [00164], [00165], [00221]. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d).
Response to Arguments
Applicant’s arguments, see Applicant Reply page 14, para. 9, filed 4/7/2026, with respect to the drawings have been fully considered and are persuasive. The objection to the drawings has been withdrawn.
Specification
The specification was previously objected to because of the proper citation of trademarks.
Applicant’s arguments, see Applicant Reply page 15, para. 3, filed 4/7/2026, with respect to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Claim Status
Claims 1, 4-19 and 21-22 are pending. Claims 1, 4-19 and 21-22 are under examination. Claims 2, 3, and 20 are canceled. Claim 22 is new.
Claim Objections
Claim 14 was previously objected to because of the following informalities. Sequences are present that lack sequence identifiers as required by 37 CFR 1.821(d). Appropriate correction is required.
Claims 18-21 was previously objected to for lacking the “withdrawn” status identifier, despite being withdrawn in the reply filed 6/20/2025. Appropriate correction is required.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 15, para. 3, with respect to claims 14, 18-19, and 21 have been fully considered and are persuasive. The objection to claims 14, 18-19, and 21 has been withdrawn. Claim 20 is canceled, rendering that objection moot.
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, 6, and 16 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, and 16 of copending Application No. 18,268,951 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Response to Arguments
Applicant’s arguments, see Applicant Reply page 15, para. 6, with respect to claims 1, 2, 6, and 16 have been fully considered and are persuasive. The rejection of claims 1, 6, and 16 has been withdrawn. Claim 2 is canceled, rendering that rejection moot.
New 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.
Claim 18, 19, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating non-acute pain that is responsive to agonism of the kappa opioid receptor or the delta opioid receptor, does not reasonably provide enablement for treatment of any possible pain, nor prevention of any kind of pain. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states: “In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is ‘reasonable’ or is ‘undue.’”
These factors include, but are not limited to:
The breadth of the claims;
Claim 18 refers to a finite set of molecules, but it is broad in that it claims prevention and treatment of any possible kind of pain.
The nature of the invention;
The invention is a method of preventing or treating pain using a compound of claim 1.
The state of the prior art;
The kappa and delta opioid receptors have been the subject of a substantial amount of study and experimentation.
Spahn et al. (Spahn, et al. Expert opinion on investigational drugs 26.2: 155-160 (2017)) discloses that targeting the delta receptor is not particularly efficacious against acute pain and its activity is centralized around the spinal cord:
“The anatomical expression pattern of DOR (cerebral cortex, striatum, amygdala, brainstem nuclei associated with pain processing, spinal cord, and dorsal root ganglia) indicates an involvement of DOR in pain regulation [Citation24]. The activation of DOR was ineffective in the modulation of acute nociception but showed analgesic actions in experimental models of persistent pain. In particular, it was demonstrated that chronic inflammation of peripheral tissue upregulates DOR in the spinal cord.” (Spahn et al., page 156, col. 1, para. 1).
Cahill et al. (Cahill, et al. Frontiers in pharmacology 5:253 (2014)) discloses a similar limitation for the kappa receptor:
“Both acute visceral pain (via intraperitoneal injection of lactic acid) and tonic pain (intraplantar injection of formalin) caused reduction in NAc dopamine release and a depression of ICSS, which was not recovered by pretreatment with a KOR antagonist. These studies highlight the influence of pain on dopamine transmission but argue that KOR is not involved in regulation of dopaminergic transmission by an acute or tonic pain stimulus within relatively short time periods.” (Cahill et al., page 9, col. 1, para. 2).
The level of one of ordinary skill;
One of ordinary skill in the art is high; typically a master’s level education or higher.
The level of predictability in the art;
The predictability of protein-protein interactions is low. A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
The amount of direction provided by the inventor and the existence of working examples; and The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant provides evidence that the molecules of claim 1 are capable of agonizing kappa opioid receptor and delta opioid receptor. Any therapeutic activity flows from this agonism activity. No actual pain data was collected from subjects.
Regarding claim 18, claim 18 recites a method of treating or preventing pain in a subject including the step of administering a therapeutically effective amount of a compound of claim 1 to thereby treat or prevent pain.
As described above, no evidence is provided for preventing pain and prevention of pain does not flow from receptor agonism of kappa or delta opioid receptors.
Regarding the nature of pain to be treated, Spahn and Cahill disclose that these receptors are not effective against pain that is acute in nature as described above.
It would require undue experimentation for a person of ordinary skill in the art to test the molecules against all possible pain types, especially acute pain and to test for prevention of pain.
Consequently, claim 18 is rejected.
Regarding claim 19, claim 18 is rejected as described above. Claim 19 further recites the case wherein the subject is a mammalian subject.
A mammalian subject does not change the analysis of claim 18, especially because most if not all of that data was collected in mammalian models.
Consequently, claim 19 is rejected.
Regarding claim 21, claim 18 is rejected as described above. Claim 21 further recites the case wherein the pain is selected from the group consisting of nociceptive pain, somatic pain, visceral pain, neuropathic pain, pain syndrome, diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia, post-stroke pain, complex regional pain syndrome, reflex sympathetic dystrophy, causalgias, cancer pain, acute pain, chronic pain, inflammatory pain and psychogenic pain.
As described above, delta and kappa opioid receptors are not particularly efficacious for nociceptive pain or acute pain. Chronic pain would be enabled once claim 18 is properly amended.
The other recited pain types in this claim would be enabled for non-acute chronic conditions once claim 18 is properly amended.
Consequently, claim 21 is rejected.
Allowable Subject Matter
Claims 1, 4-17, and 22 are allowable over the prior art. The closest prior art is described below:
From a conceptual standpoint, Fang et al. (Fang, et al. Journal of medicinal chemistry 52.18: 5619-5625. (2009)) describes Dynorphin A analogues which are cyclized via ring closing metathesis, resulting in linkers characterized by double bonds: “We utilized ring-closing metathesis (RCM) in the design and synthesis of new cyclic Dyn A analogues.” (Fang et al., page 5620, col. 1, para. 2).
Examples:
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550
306
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(Fang et al., page 5620, Figure 1)
Furthermore, Fang discusses the potential usage of a disulfide-based linkage in a negative light: “Compared with peptides cyclized by amide or disulfide bond formation, there are some advantages to using RCM. The resulting carbon-carbon bond is more stable than a disulfide or an amide bond.” (Fang et al., page 5620, col. 1, para. 2), which constitutes a teaching away from the disclosed invention.
Regarding the linker itself, no qualifying prior art discloses the claimed linker structure in a manner that would teach or suggest to a person of ordinary skill in the art for usage in peptide stabilization.
Conclusion
Claims 18, 19, and 21 are rejected.
Claims 1, 4-17, and 22 are allowable.
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.
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 David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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