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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. The amendments filed on May 6, 2026 have been entered.
Reissue: Final Office Action after RCE
Prosecution History and Claim Status
On 4/21/2020 US Patent 10,624,945 issued to Ruff with claims 1-10. On 3/18/2022 applicant filed US. Reissue Patent Application 17/698,065 (now RE50,630) for US. Patent 10,624,945. On 7/21/2022 applicant filed US Reissue Patent Application 17/869,925 for US Patent 10,624,945, which is a CON of Reissue Application 17/698,065.
Claims 11-26 were filed as new claims in the instant reissue application. The amendment dated 12/1/2025 cancelled claims 11-19. Claims 20-26 are currently pending and are the subject of this Office Action.
REJECTIONS WITHDRAWN
The rejection of claims 20-26 under 35 U.S.C. 112(b) is withdrawn in light of the claim amendments.
OBJECTIONS/REJECTIONS MAINTAINED
The rejection of claims 20-26 under 35 U.S.C. 103 is maintained as discussed below.
Maintenance Fees
Applicant is reminded of the requirement to pay all applicable maintenance fees on the original patent. See MPEP § 1415.01.
Ongoing Duty To Disclose
Applicant(s) is/are reminded of the continuing obligation under 37 CFR 1.178(b), to timely apprise the Office of any prior or concurrent proceeding in which Patent 10,624,945 is or was involved. These proceedings would include any trial at the Patent Trial and Appeal Board, interferences, reissues, reexaminations, supplemental examinations, and litigation.
Applicant is further reminded of the continuing obligation under 37 CFR 1.56, to timely apprise the Office of any information which is material to patentability of the claims under consideration in this reissue application.
These obligations rest with each individual associated with the filing and prosecution of this application for reissue. See also MPEP §§ 1404, 1442.01 and 1442.04.
Multiple Reissue Applications
The instant case is a (reissue) CON of reissue application 17/698,065 (now RE50,630). 37 CFR 1.177(a) requires that all multiple reissue applications resulting from a single patent must include as the first sentence of their respective specifications a cross reference to the other reissue application(s). Accordingly, the first sentence of each reissue specification must provide notice stating that more than one reissue application has been filed, and it must identify each of the reissue applications and their relationship within the family of reissue applications, and to the original patent. An example of the suggested language to be inserted is as follows:
Notice: More than one reissue application has been filed for the reissue of Patent No. 99,999,999. The reissue applications are application number 99/999,994 (the present application); and application number 99/999,995, which is a continuation reissue of Patent No. 99,999,999.
See MPEP § 1451. Applicant should file a certificate of correction in the underlying patent (RE50,630) to inform the public of the presence of this application.
Claim Rejections - 35 USC § 103 (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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 20-26 are rejected under 35 U.S.C. 103 as being unpatentable over PERT (US 2011/0245180), RUFF (US 2014/0323393), LI (Li, X., et al. Ann. Palliat. Med. (2012), 1(1); 14-31; on 12/11/24 IDS), and KWIATKOWSKI (Kwiatkowski, K., et al. J. Neuroimmune Pharmacol. (2017), 12; 402-419).
Claims 20-26 are composition claims that require a DAPTA peptide (having structure A-B-C-D-E as defined in the claim), an opioid, and a pharmaceutically acceptable carrier. As discussed below, Pert and Ruff teach compositions comprising DAPTA peptides without the inclusion of an opioid. However, Li establishes the longtime use of opioids in the treatment of neuropathic pain, particularly post-surgical pain. As in In re Kerkhoven (below), the inclusion/administration of opioid for this same purpose would have been prima facie obvious to one of skill in the art. Kwiatkowski establishes the motivation/expectation of using less opioid in a composition comprising a C-C chemokine receptor type 2 (CCR2) antagonist such as DAPTA peptides. The claimed invention would have been an obvious modification of these references.
Pert teaches a method of treating a post-surgical pain in a patient comprising administering a therapeutically effective dose of the chemokine receptor antagonist DAPTA, an octapeptide derived from HIV gp120, particularly all-D or TTNYT (SEQ ID NO:1), which is a D peptide of formula A-B-C-D-E, (abstract; [0003]-[0004], [0007], [0023], [0035], [0050]-[0080]). Pert teaches compositions comprising a pharmaceutically acceptable carrier (claims 1, 4, 7). Pert teaches a post-surgical model, particularly partial ligation of the sciatic nerve ([0003], [0017], [0023], [0035], [0038]-[0043], [0050], [0061], [0063], [0067]). Pert teaches chemokine signaling is important in neuropathic pain, with microglial cells expressing CCR2 playing a well-established key role. DAPTA is taught to exhibit potent antagonism for CCR2 (abstract; [0058]-[0060], [0068]). Pharmacological blockade by All-D TTNYT of CCR2 has therapeutic potential in injury associated-neuropathic pain ([0072], [0082]).
Ruff teaches managing pain in patients with brain injury and disease including from neuropathy, nerve injury, trauma and inflammation ([0002], [0008], [0010]-[0012], [0027]-[0045], [0047], [0049], [0094], [0099]; claims 2-3 and 11). Ruff teaches administering a composition comprising peptides of the recited formula A-H and/or C-H, 5-8 amino acids, which correspond to the recited peptides of formula A-E including All-D-TTNYT corresponding to claimed SEQ ID NO:1, All-D ASTTTNYT, and all-D DAPTA (Ruff SEQ ID NO:1-10, [0078]-[0079], claim 1).
Both Ruff and Pert recognize the benefit of the DAPTA peptide all-D TTNYT via the same mechanisms within post-surgical nerve injury pain, including particularly trauma, inflammation and binding at DAPTA pain receptors (i.e., CCR2). Specifically, Ruff teaches that DAPTA blocks CCR2 (i.e., DAPTA is a CCR2 antagonist) ([0083]-[0084], [0087]-[0088], [0099]; Table 1). Ruff taches treating pain in a nerve injury model ([0094]), which Pert teaches is a post-surgical nerve injury model as described above. Accordingly, one of skill in the art would have prepared DAPTA-containing compositions to treat post-surgical pain as exemplified within Ruff and Pert, particularly with all-D DAPTA peptide TTNYT (SEQ ID NO:1) for nociceptive effect as recognized in the art.
Pert and Ruff do not teach administration of opioids in combination with the peptides.
However, Li reviews advances in the use of opioids in treating neuropathic cancer pain (title; abstract), as well as the longstanding use of opioids treating nerve-injury pain. Li teaches that morphine and other opioids (e.g. oxycodone, fentanyl, methadone, tapentadol, tramadol, etc.) were known to effectively relieve neuropathic pain (including peripheral neuropathic pain) (pgs. 53-57).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared a composition comprising all-D TTNYT (DAPTA) or all-D ASTTTNYT in combination with opioids and a pharmaceutically acceptable carrier, for use in the treatment of neuropathic pain.
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). See MPEP § 2144.06(I).
In this case, both the all-D DAPTA peptide (all-D TTNYT or ASTTTNYT) and various opioids were known in the art for the treatment of neuropathic pain (according to Pert, Ruff, and Li). Therefore, it would have been prima facie obvious to combine all-D DAPTA peptides with opioid(s) as active agents along with a pharmaceutically acceptable carrier to prepare a composition for the treatment of neuropathic pain (e.g., pain associated with post-surgical nerve injury).
Regarding the recitation "wherein said amount is less than the amount of the same opioid required to achieve an equivalent analgesic effect when administered in the absence of the D peptide or the DAPTA under otherwise identical conditions," Kwiatkowski reports on the effect of a CCR2 antagonist (RS504393) on pain and its influence on opioid effectiveness (title; abstract). Like Pert and Ruff, Kwiatkowski teaches that C-C motif chemokine ligand 2 (CCL2) and its receptor C-C chemokine receptor type 2 (CCR2) play crucial roles in neuropathic pain development (p. 403, 1st col.). Administration of the CCR2 antagonist attenuated pain response in a model of neuropathic pain (p. 406, 2nd col.; Fig. 2; Discussion) and, critical to the examined claims, enhanced the analgesic properties of opioids (morphine and buprenorphine) under neuropathic conditions (abstract; p. 410, 2nd col.; Fig. 7; Discussion). Kwiatkowski teaches that CCR2 antagonism diminishes neuropathic pain and enhances opioid analgesic effects (abstract; Conclusion).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared a composition comprising an all-D DAPTA peptide in combination with an opioid. In doing so, one would have been motivated to include less opioid than in an equivalent composition not comprising the all-D DAPTA peptide because Kwiatkowski teaches that CCR2 antagonists (like all-D DAPTA peptides) enhance opioid analgesic potency. Thus, when combining a CCR2 antagonist and an opioid, the artisan would have expected less opioid would be required to achieve the same analgesic effect. Including less opioid would have been recognized as beneficial since opioids are well-known to cause dependence, leading to addiction.
Regarding claims 20-22, the all D TTNYT (SEQ ID NO:1) is a peptide in which the amino acids are all in the D stereoisomeric configuration (see Pert at pars. [0005], [0069]-[0070]). See also Ruff, teaching that all-D TTNYT or ASTTTNYT is SEQ ID NO:1 in which the amino acids are in the D stereoisomeric configuration (abstract, [0049], [0073]-[0075]]).
Regarding claim 23, all-D TTNYT DAPTA are C-terminally amidated peptides (see Ruff at pars. [0049], [0074]).
Regarding claims 24-26, Pert is specific to liquid compositions, whereas Ruff also includes pill compositions.
Regarding claims 24-25 the pharmaceutical composition is at a therapeutically effective dose to be administered orally in water (liquid saline) and in tablet form (i.e., a pill) at 0.05-500 mg (see Ruff abstract, [0056], [0058]-[0059], [0063], [0082]-[0083], [0085], [0092], [0096]).
Regarding claim 26, the pharmaceutical composition taught by Pert is liquid at 0.05-1 mg/kg in sterile water (liquid form), including for oral administration (abstract, [0014]-[0016], [0020]-[0021], [0040]-[0042], [0061]-[0062], [0072], [0074]).
Response to Arguments
Applicant's arguments have been fully considered but are not persuasive. Applicant argues that the cited references do not teach the element of claim 20 reciting that the opioid is present in an amount less than the amount [of opioid] required to achieve an equivalent analgesic effect in the absence of the D peptide or the DAPTA (response, p. 9).
The teachings of Kwiatkowski meet this limitation. Specifically, Kwiatkowski teaches that CCR2 antagonists attenuated pain response in a model of neuropathic pain (p. 406, 2nd col.; Fig. 2; Discussion) and, critical to the examined claims, enhanced the analgesic properties of opioids (morphine and buprenorphine) under neuropathic conditions (abstract; p. 410, 2nd col.; Fig. 7; Discussion). Kwiatkowski teaches that CCR2 antagonism diminishes neuropathic pain and enhances opioid analgesic effects (abstract; Conclusion).
While Kwiatkowski does not use the exact same verbiage as in the claims, an artisan of ordinary skill would have understood that enhancing the analgesic effect of an opioid allows for the use of less of that opioid. Including less opioid would have been recognized as beneficial since opioids are well-known to cause dependence, leading to addiction. Kwiatkowski directly provides motivation to use less opioid by teaching that treatment of neuropathic pain is a serious clinical problem, in part because of numerous undesired adverse effects of opioids that are commonly used in high doses (first sentence of the Introduction). Lower doses of opioids are clearly desirable. Based on Kwiatkowski, one would have been motivated to include less opioid than in an equivalent composition not comprising the all-D DAPTA peptide because Kwiatkowski teaches that CCR2 antagonists (like all-D DAPTA peptides) enhance opioid analgesic potency. By administering an all-D DAPTA peptide (a known CCR2 antagonist) in combination with an opioid, one would expect an enhanced analgesic effect (per Kwiatkowski), and would thus know that less opioid would be required to achieve the same analgesic effect than in the absence of the all-D DAPTA peptide.
Applicant argues that an increase in analgesic effect is different from achieving the same analgesic effect at a reduced dose. Applicant argues that the references do not provide a reason to reduce the amount administered (response, p. 9).
Using less of an opioid under a condition (e.g., coadministration with a CCR2 antagonist) in which the opioid activity is enhanced is the corollary to enhanced analgesic effect. A "motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill." (emphasis added) See MPEP § 2143.01. Using less opioid under conditions where opioid activity is enhanced would have been a matter of common sense to a skilled artisan. Doing so is further motivated by Kwiatkowski, who attributes problems with treatment of neuropathic pain to the high doses of opioids that are commonly used (first sentence of the Introduction). Thus, in addition to the knowledge of the skilled artisan, Kwiatkowski provides a teaching to lead an artisan to reduce the amount of opioid when co-administering it with a CCR2 antagonist. Furthermore, Kwiatkowski teaches that the pharmacological modulation of CCR2 may represent a new strategy for effective polytherapy with opioids in patients suffering from neuropathic pain (last sentence of Conclusion section). As understood by the artisan in this field, this teaching suggests combination therapy of opioids with CCR2 antagonists.
Applicant argues that the CCR2 antagonist tested by Kwiatkowski is different from the claimed all-D DAPTA peptides (response, pgs. 9-10).
Although Kwiatkowski focuses on a different CCR2 antagonist, Kwiatkowski’s report states that the data prove CCR2 as a promising target for diminishing neuropathic pain and enhancing opioid analgesic effects (abstract; Fig. 7b; Conclusion). This conclusion is not specific for the CCR2 antagonist tested by Kwiatkowski. Kwiatkowski establishes a reasonable expectation of success in using other known CCR2 antagonists to achieve the same result. Further, the rejection is based in obviousness, not anticipation. There is no requirement that Kwiatkowski teach the same CCR2 antagonist as Pert and Ruff.
Applicant argues that the CCR2 antagonist tested by Kwiatkowski is not a pure CCR2 antagonist (response, p. 10).
First, Kwiatkowski teaches CCR2 antagonists have the ability to enhance the analgesic effect of opioids (see Kwiatkowski, entire document). Kwiatkowski directly teaches, “We hypothesize that the beneficial properties of RS504393 resulted from antagonizing CCR2, as it has been shown in our previous paper (Piotrowska et al. 2016a) and also in other publications (Berkhout et al. 2003; Pevida et al. 2012; Zhang et al. 2012).” (p. 410, 2nd col). Thus, Kwiatkowski’s conclusions are supported by other studies as well. Even if, arguendo, the CCR2 antagonist tested by Kwiatkowski happens to have an additional affinity for other receptors, that does not take away from the fact that its CCR2 antagonism is reported to be at least partially responsible for enhancing opioid analgesia. Second, applicant’s argument is predicated on a single sentence in the reference, where Kwiatkowski speculates that α1a adrenergic receptor affinity might be relevant for the analgesic effects observed (p. 412, 1st full sentence of col. 1). In the same sentence, however, Kwiatkowski clearly states that this possibility needs to be evaluated in the future (p. 412, 1st full sentence of col. 1). Thus, this statement by no means establishes that affinity for the α1a adrenergic receptor is even relevant, let alone causative or important, for enhancing opioid analgesic effect. To the contrary, it may play no role at all. Kwiatkowski does not even refer to the enhancement of opioid analgesic effect in this statement, so Kwiatkowski may instead be referring to the other analgesic effects noted in the report. Nonetheless, applicant appears to take this speculative statement by Kwiatkowski as a foregone conclusion, while disregarding the other data and conclusions provided directly in Kwiatkowski’s report. Such speculative arguments are not sufficient to overcome the strong prima facie case of obviousness that has been established here.
Applicant argues that the claimed all-D DAPTA peptides also bind to CCR5 and CCR8, and an artisan would therefore not have had a reasonable expectation of success (response, p. 10).
There is no evidence of record that CCR5/CCR8 activity is required for the recited opioid potentiation. Pert actually teaches that CCR5 blockade is not required for the all-D DAPTA peptides ([0072]). Nonetheless, the rejection is based on the teachings of Pert, Ruff, and Kwiatkowski, which link treatment of pain to CCR2 antagonism.
Applicant argues that impermissible hindsight has been used (response, pgs. 10-11).
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). Since each and every aspect of the rejection is fully supported by the teachings of the prior art, impermissible hindsight has not been used.
Applicant argues that In re Kerkhoven does not apply, and asserts unexpected results (response, pgs. 11-13).
Given the teachings of Kwiatkowski, it was reasonably predictable, and expected, that combining an opioid with a CCR2 antagonist such as an all-D DAPTA peptide, would enhance the opioid analgesic effect. One of skill in the art would have understood that an enhanced opioid analgesic effect would allow the use of less opioid to achieve the same effect (i.e., in applicants’ parlance, the opioid dose response curve would have been expected to shift to the left). The ability to use less of the opioid when combined with an all-D DAPTA peptide is neither surprising nor unexpected.
Kwiatkowski directly provides motivation to use less opioid by teaching that treatment of neuropathic pain is a serious clinical problem, in part because of numerous undesired adverse effects of opioids that are commonly used in high doses (first sentence of the Introduction). The use of lower opioid doses is desirable in the art. Further regarding the assertion of unexpected results, the data proffered by applicant are not commensurate in scope with the instant claims. For example, the Figure on p. 12 is limited to a particular opioid administered at particular doses. The instant claims place no limitations on either the identity or dose of opioid.
Conclusion
Claims 20-26 are rejected. No claims are currently allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 Kevin S Orwig whose telephone number is (571)270-5869. The examiner can normally be reached Mon.-Fri. 8AM-5PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Patricia Engle can be reached at (571) 272-6660. The fax phone number for the organization where this application or proceeding is assigned is 571-273-9900.
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/Kevin S Orwig/Patent Reexamination Specialist, Art Unit 3991
Conferees:
/LBD/Patent Reexamination Specialist, Art Unit 3991
/Patricia L Engle/SPRS, Art Unit 3991
Prosecution Insights