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 .
Reissue: Final Office Action
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 applicants filed US. Reissue Patent Application 17/698,065 (now RE50,630) for US. Patent 10,624,945. On 7/21/2022 applicants 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.
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.
REJECTIONS WITHDRAWN
The double patenting rejections of record have been withdrawn in light of the terminal disclaimer filed and approved on 12/1/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 20-26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 20-26 are indefinite in the recitation "wherein the opioid is present in the pharmaceutical composition at an effective amount that is less than an effective amount of an opioid present in a pharmaceutical composition lacking the D peptide or DAPTA" in claim 20. This limitation is indefinite because the claim does not specify (1) the required effect for "an effective amount" of said opioid or (2) an actual amount of opioid in the composition lacking the D peptide/DAPTA. Regarding (1), the specification never uses, let alone defines, the term "effective amount". Thus, it is unclear what the amount must be effective to do. While one might reasonably presume that the effect is treatment of pain generally, the effect could be any number of other outcomes, such as treatment of one of a variety of specific types of pain (e.g., chronic, acute, inflammatory, neuropathic, etc.), mitigation of opioid withdrawal symptoms (e.g., in a patient with opioid use disorder), management of dyspnea, etc. See MPEP § 2173.05(c)(III).
Further, the claim uses the phrase "an effective amount" (emphasis added). Thus, the two "effective amounts" recited in the claim are not correlated with one another whatsoever. For example, the amount of opioid present in a DAPTA-containing composition intended for use in opioid-naïve children would be less than an opioid containing composition intended for use in an opioid tolerant adult, regardless of the presence or absence of a DAPTA peptide. Yet the DAPTA/opioid composition for children in this scenario could be compared to any other opioid containing composition (e.g., one intended for use in an opioid tolerant adult because it is "a pharmaceutical composition lacking the D peptide or DAPTA"), and still meet the claim.
Regarding (2), the claim refers to an undefined pharmaceutical composition lacking the D peptide or DAPTA. The amount of opioid in this undefined composition is not limited to a minimum amount of opioid (e.g., a minimum effective amount), and thus could contain any amount of opioid that exerts any effect. Thus, one of ordinary skill in the art could reasonably construe the "effective amount" to be any of a variety of subjective amounts depending on what arbitrary DAPTA-free opioid composition is used as a comparison, and depending on what subjective effect is selected by the artisan. Since one of ordinary skill in the art could not be expected to make a reasonable distinction in the absence of further definitions and/or guidance in the specification, the metes and bounds of these claims are indefinite.
The Federal Circuit has noted that "the patent drafter is in the best position to resolve the ambiguity in the patent claims, and it is highly desirable that patent examiners demand that applicants do so in appropriate circumstances so that the patent can be amended during prosecution rather than attempting to resolve the ambiguity in litigation." Halliburton Energy Servs., 514 F.3d at 1255 (Fed. Cir. 2008). Claims 21-26 depend from claim 20 and do not resolve the ambiguity. As such, claims 20-26 must be rejected under 35 U.S.C. 112(b).
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.
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). This rejection addresses the interpretation of the “wherein” clause at lines 12-15 of claim 20 as requiring that the combined effective amounts would treat pain upon administration to a subject. Furthermore, the claim is interpreted as requiring that included amount of opioid in the combination composition is less than would be required were the opioid administered alone.
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 does not disclose treating pain that is post-surgical. However, Ruff is explicit to 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 the opioid is present in the pharmaceutical composition at an effective amount that is less than an effective amount of an opioid present in a pharmaceutical composition lacking the D peptide or DAPTA," Kwiatkowski reports on the effect of a CCR2 antagonist (RS504393) on pain and its influence on opioid effectiveness (title; abstract). Like Pert, 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 to require less opioid 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 claim 20 has been amended to recite, "wherein the opioid is present in the pharmaceutical composition at an effective amount that is less than an effective amount of an opioid present in a pharmaceutical composition lacking the D peptide or DAPTA". Applicant argues that none of Pert, Ruff, and Li teach a lesser dose of an opioid could be used in combination with a DAPTA peptide (response, pgs. 6-7).
As discussed above, the new “wherein” clause is indefinite (see the 112(b) rejection set forth above). For the consideration of prior art, however, it has been interpreted as requiring that the combined effective amounts would treat pain (generally) upon administration to a subject. It is also interpreted as requiring that the included amount of opioid in the combination composition is less than would be required were the opioid administered in an otherwise identical composition lacking a D peptide or DAPTA. This interpretation is addressed by Kwiatkowski. Kwiatkowski teaches that administration of a CCR2 antagonist attenuated pain response in a model of neuropathic pain (p. 406, 2nd col.; Fig. 2; Discussion) and enhanced the analgesic properties of opioids (morphine and buprenorphine) under neuropathic-pain conditions (abstract; p. 410, 2nd col.; Fig. 7; Discussion). Kwiatkowski teaches that CCR2 is a target for diminishing neuropathic pain and enhancing opioid analgesic effects (abstract; Conclusion). Thus, one of ordinary skill in the art would have known to include less opioid in combination with a CCR2 antagonist like the all-D DAPTA peptides, and would have expected to enhance the opioid analgesic effect due to the combination.
Applicant argues that the ability to use less of the opioid when combined with a DAPTA peptide is surprising and unexpected (response, pgs. 7-12).
The teachings of Kwiatkowski, however, establish the expectation of enhancing the opioid’s analgesic effect when used in combination with a CCR2 antagonist, such as the all-D DAPTA peptides. Thus, the ability to use less of the opioid when combined with an all-D DAPTA peptide is neither surprising nor unexpected.
Summary/Conclusion
Claims 20-26 are rejected; claims 1-19 are cancelled.
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 extension fee 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 date of this final action.
Contact Information
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