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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 15, 2025 has been entered.
Election/Restrictions
As previously discussed, Applicants elected without traverse Group 1 and the species of a PGE2 compound that inactivates or blocks the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (claim 5), the myotoxin that is an amino-amide anaesthetic that is bupivacaine (claims 6-8), muscle atrophy (claim 17) and spinal muscle/muscular atrophy (claim 18). Claim 1 has been amended. Claims 2-4 and 20-23 have been canceled. No claims have been added. Claims 9-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, non-elected species, there being no allowable generic or linking claim. Claims 1, 5-8 and 14-19 are examined on the merits herewith.
Claim Rejections - 35 USC § 112, (b)
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 5-8 and 14-19 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims are indefinite, because they are vague and not delimited. Claim 1 has been amended to recite that the amount of the composition comprising the myotoxin/bupivacaine and the PGE2/15-PGDH inactivator or blocker is an amount that regenerates stem cells in a muscle of a subject having a muscle condition (condition meaning disease or damage), but the claims do not recite what this amount is. What is the amount of the composition, or the amount of the myotoxin/bupivacaine, or the amount of the PGE2/15-PGDH inactivator or blocker? Quantities, even as numerical ranges, are required for definite claim language. Clarification and appropriate correction are required.
To expedite greatly prosecution for Applicants, which Applicants may or may not want, claim 1 may be amended to recite a second wherein clause, wherein the amount of the myotoxin is a therapeutically effective amount (or volume) at a concentration of at least 0.25% and the amount of the compound that attenuates the PGE2 catabolism is a therapeutically effective amount (or volume) at a concentration of at least 0.4 mg/ml (20 pg/50 pl) or in an amount of at least 20 pg per dose. See paragraphs 110, 592 and 593 (Example 8) of the specification.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendments to the claims, the rejections in the previous Office action have been modified to mirror the amended claim set.
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.
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.
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 as of the effective filing date of the claimed invention(s) 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 as of the effective filing date of the later invention 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.
Claim(s) 1, 5-8 and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Shen et al. (“Inhibited skeletal muscle healing in cyclooxygenase-2 gene- deficient mice: the role of PGE2 and PGF2α ,” J Appl Physiol 101:1215-1221, 2006), cited in Applicants’ IDS of Dec. 27, 2023; Miller et al. (“Bupivacaine injection remodels extraocular muscles and corrects comitant strabismus,” Ophthalmology 120(12):2733-2740, 2013, cited in Applicants’ IDS of Dec. 27, 2023; and Kishore et al. (“Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms,” 99(3):1006-1018, 2014).
The claims were previously amended to recite that the compound that decreases (referred to by Applicants as “attenuates”) PGE2 catabolism is a small molecule that inactivates or blocks the enzyme 15-PGDH (15-hydroxyprostaglandin dehydrogenase). See claim 5. The specification discloses in paragraphs 25, 26, 28, 31, 38 and 81 that a compound/small molecule that decreases the activity of (inactivates or blocks) 15-PDGH is PGE2 itself.
As previously discussed, Kishore et al. disclose that PGE2 represses, i.e., decreases the activity and the level of 15-PDGH, by down-regulating 15-PDGH gene expression, via a mechanism involving EP2 receptors. See pp. 1006 – 1009, including Fig. 1 on p. 1008. Thus, PGE2 is a compound and small molecule that reduces/attenuates PGE2 catabolism, by blocking 15-PGDH. If the gene expression is blocked, expression and synthesis of the encoded enzyme is blocked, and the attenuation/decrease of PGE2 catabolism is blocked. Consequently, the claim scope of the amended claims is the same as before the most recent amendment.
As previously discussed, Shen et al. disclose that PGE2 is a prostaglandin inhibitor and pro-inflammatory molecule that is therapeutically effective for muscle regeneration and muscle healing. It can treat muscle injuries and the pain associated with them, such as muscle injuries from sports and athletic endeavors. The pro-inflammatory activity causes chemotaxis of inflammatory cells, macrophages in particular, which are important mediators of the muscle regenerative process. The mode of action is that it is a COX-2 inhibitor. See pp. 1215 – 1218, including Table 2 on p. 1217, and 1220. The specification discloses that one of the main molecules that is a PGE2 that attenuates PGE2 catabolism and that is a 15-hydroxyprostaglandin dehydrogenase inactivator or blocker is PGE2; see paragraphs 26, 28, 29, 31 and 81 of the specification. See claims 1, 5, 14 and 17-19. Shen et al. disclose a pharmaceutical composition comprising PGE2 in a pharmaceutically acceptable excipient, Ringer’s solution (see p. 1217, right col.) or cell culture medium that lacks serum (see p. 1216, right col.). See claims 15 and 16. Ringer’s solution can be used to make a preparation for intramuscular injection.
Miller et al. disclose a composition comprising bupivacaine, an amino-amide anaesthetic, and that bupivacaine can be injected into skeletal muscles, to treat a muscle condition that is muscle damage, strabismus, mis-aligned muscles in the eyes. It destroys the myofibrillar system while preserving intact satellite cells, basal lamina, capillaries and peripheral nerves. Within a few weeks, the muscle rebuilds and, generally, it is increased in size. The recovered muscle has normal morphology and function, and it undergoes hypertrophy, resulting in a muscle with increased total contractile force. Bupivacaine can be used to treat strabismus with good clinical results, including improved eye alignment. See p. 2 and 4 – 6 of 11. Miller et al. do not disclose the pharmaceutically acceptable excipient explicitly, but they note that they used a commercially available preparation, Leiter’s Rx compounding, San Jose, CA (see pp. 3-4 of 11). See claims 6-8 and 15-18. Thus, the artisan of ordinary skill at the time that the invention was filed would have known that the bupivacaine was prepared in a pharmaceutically acceptable excipient that is suitable for intramuscular injection.
Regarding the new limitation in claim 1, the wherein clause, as discussed above, the amount of the composition that regenerates muscle stem cells in muscle tissue is indefinite and can be anything, as it is not recited in the claims. The composition comprises any myotoxin and any compound that attenuates PGE2 catabolism. This wherein clause does not further limit the claims, or render them patentable.
It would have been obvious to the artisan of ordinary skill at the time that the invention was filed to combine the teachings of the references so as to make a composition comprising PGE2 and bupivacaine, for treating a muscle condition, muscle injury or muscle damage, to restore and repair the muscles, because each of the agents has been individually taught in the prior art to be successful for this purpose. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980), wherein the court held that 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 for a third composition that is to be used for the very same purpose, since the idea of combining them flows logically from their having been individually taught in the prior art. See MPEP §2144.06. One of ordinary skill in the art would have reasonably expected to have been able to combine the teachings of these references to arrive at this therapeutic composition comprising PGE2 and bupivacaine, for treating muscle injuries or muscle damage. Additionally, this artisan of ordinary skill would have known that, by combining the teachings of the cited references, the composition would have contained two therapeutic agents, instead of one, each of which has a different mode of action (bupivaine works by regenerating muscle fibers; see p. 8 of 11 of Miller et al.), for an improved effect on muscle healing. This artisan of ordinary skill would have known that each person responds differently to each drug or therapeutic agent, and that, as a result, a therapeutic composition comprising two therapeutic agents would have a better chance of being effective in each person than a therapeutic composition comprising a single therapeutic agent. Similarly, this artisan of ordinary skill would have known that a therapeutic composition comprising two therapeutic agents would likely be effective in a larger percentage of the people taking or consuming if than a therapeutic composition comprising a single therapeutic agent.
In view of the foregoing, a holding of obviousness is required.
The elected species of treating spinal muscular atrophy in claim 18 is free of the prior art, as the references discussed above do not disclose treating spinal muscle atrophy. Strabismus is a disease/condition in which the muscles of the eye are misaligned, too far up or down or to the right or to the left, but it is not a disease of muscular atrophy.
Applicants assert that the claimed invention is not obvious, because the specification does not disclose that PGE2 is an inactivator/blocker of 15-PGDH, Kishore et al. disclose that PGE2 acts to decrease the level of 15-PGDH in cervical stromal cells via a mechanism involving MiTF-CX and the prostaglandin E2 receptor, and Shen et al. do not disclose that PGE2 is an inactivator/blocker of 15-PGDH. Applicants’ Expert Declaration repeats the arguments in the Response with respect to the Kishore et al. reference.
In reply, as discussed above, the specification discloses in paragraphs 25, 26, 28, 29, 31, 38 and 81 that the PGE2 compound is PGE2. The PGE2 compound is one of a set of eight categories of compounds, one of the categories being a compound that inactivates or blocks 15-PGDH. This argument is not persuasive of non-obviousness or patentability.
Regarding Kishore et al., Applicants argue the method of use. The instant claims are very broad composition claims; they are not drawn to the method of use. Applicants may wish to file a divisional application, with claims drawn to a method of regenerating stem cells in damaged or diseased muscle tissue, by administering to the site of the damaged or diseased muscle tissue in a subject in need thereof a composition comprising therapeutically effective amounts of a myotoxin (or bupivacaine) and PGE2 (or a compound that inactivates or blocks 15-PGDH. Applicants argue that Kishore et al. studied a different type of cells than Applicants did, and that, in these cells, PGE2 (the 15-PGDH inactivator/blocker) works by a different mechanism than in muscle cells for regenerating muscle stem cells (a mechanism involving prostaglandin EP4 receptors, rather than prostaglandin EP2 receptors). Again, however, Kishore et al. were cited for the disclosure that PGE2 is an inactivator/blocker of 15-PGDH, and the claims are composition claims, not method of use claims. The mode of action in the method of Kishore et al. has no bearing on the patentability of the instant claims. Applicants’ arguments and Expert Declaration are not persuasive.
Regarding Shen et al., as noted above, the reference was cited for the disclosure that PGE2 is a prostaglandin inhibitor and pro-inflammatory molecule that is therapeutically effective for muscle regeneration and muscle healing. It can treat muscle injuries and the associated pain, such as muscle injuries from sports and athletic endeavors. The pro-inflammatory activity causes chemotaxis of inflammatory cells, macrophages in particular, which are important mediators of the muscle regenerative process. The reference was not cited for the disclosure that PGE2 is an inactivator/blocker of 15-PGDH. Applicants’ arguments are not persuasive.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROSANNE KOSSON whose telephone number is (571)272-2923. The examiner can normally be reached M, T, Th- 9-6; W- 9-2.
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/ROSANNE KOSSON/
Primary Examiner, Art Unit 1759
2025-07-21