DETAILED ACTION
Notice of 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 .
Status of the Claims
The amendments filed 10/10/2025 have been entered.
Response to Arguments
Applicant’s arguments, filed 10/10/2025, have been fully considered.
Applicant traverses the rejection of claims under 35 U.S.C. 103(a). As noted by Applicant, the rejection reasons that it would have been obvious to administer a therapeutically effective amount of a 15-PGDH inhibitor to a subject having Duchenne muscular dystrophy in order to increase myoblast proliferation in said subject and, thereby, regenerate muscle (Applicant Arguments, Page 6). Yet, as argued by Applicant, “[t]he Office has not provided any evidence that increasing myoblast proliferation alone, independent of activating muscle stem cells, is sufficient to regenerate muscle in vivo” (Applicant Arguments, Page 6). As further argued by Applicant, “even the references cited by the Office appear to agree that muscle regeneration is dependent on the activation of muscle stem cells” (Applicant Arguments, Page 6).
The argument is not found persuasive. As discussed in the basis of the rejection, “the maintenance and repair of adult skeletal muscle” is governed by “[m]uscle precursor cells, known as satellite cells” which “are quiescent in nature [but] respond to regenerative cues such as physical damage and exercise by undergoing cycles of proliferation” – at which point they are termed myogenic precursor cells or myoblasts – “before terminally differentiating into multinucleated myofibers” (Page 2064, Column 1). While it is acknowledged that Shi et al and Sienkiewicz et al each intervene to increase satellite cell proliferation in promoting muscle regeneration, the interventions of Shi et al and Sienkiewicz et al both result in and require increased myoblast proliferation to achieve muscle regeneration, and nowhere do Shi et al or Sienkiewicz et al suggest that the increase in satellite cell proliferation is acting through some other mechanism independent of increased myoblast proliferation in promoting muscle regeneration. As such, it is MAINTAINED that a person of ordinary skill in the art would reason that intervening downstream of satellite cells in the pathway of muscle regeneration by directly increasing myoblast proliferation would similarly promote muscle regeneration, with a reasonable expectation of success.
Applicant next argues that “it was unknown that muscle stem cells express the prostaglandin receptor EP4 and can be activated by PGE2” (Applicant Arguments, Page 7) and, “[a]ccordingly, a person of ordinary skill in the art would not have understood that PGE2 signaling could cause muscle stem cell activation through EP4” (Applicant Arguments, Page 8).
However, it is not necessary that the prior art suggest the combination of references to achieve the same advantage or result discovered by Applicant (in this case, to promote satellite cell proliferation through EP4). Rather, the reason or motivation to modify a reference to arrive at the claimed invention can be for a different purpose or to solve a different problem (in this case, to increase PGE2 levels and signaling to enhance myoblast proliferation). See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention). The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58 (Bd. Pat. App. & Inter. 1985).
Applicant next argues that “[a] person of ordinary skill in the art would not have selected 15-PGDH inhibition as a therapeutic approach for regenerating muscle” (Applicant Arguments, Page 8). As argued by Applicant, “[t]he expression of 15-PGDH in muscle is neither taught nor suggested by any of the cited references” and “[a]bsent the knowledge that 15-PGDH is expressed in muscle, it would not have been obvious to a person of ordinary skill in the art to use a 15-PGDH inhibitor to increase PGE2 levels in muscle and to activate muscle stem cells” (Applicant Arguments, Page 9). Although Applicant acknowledges that “Zhang teaches a small molecule inhibitor of 15-PGDH (SW033291)… increases PGE2 levels in bone marrow and other tissues”, Applicant argues that “Zhang does not disclose or suggest that a small molecule inhibitor of 15-PGDH would increase PGE2 in muscle, or that 15-PGDH is even expressed in muscle” (Applicant Arguments, Page 9).
The argument is not found persuasive. As discussed in the basis of the rejection, Mo et al teach that “PGE2 [prostaglandin E2] signaling… regulates myogenesis by promoting myoblast proliferation” (Abstract; see also Page 1512, Column 1: “PGE2 signaling is important for both myoblast proliferation and differentiation, the 2 critical steps for muscle development and regeneration”) and “PGE2 signaling… could have significant implications in a number of pathological disorders, such as muscle atrophy [and] muscular dystrophies” (Page 1513, Column 2). It is MAINTAINED that it would have been obvious to administer a therapeutically effective amount of a 15-PGDH inhibitor (such as, for example, the small molecule compound SW033291) to promote PGE2 signaling in muscle considering that Zhang et al teach “inhibition of 15-PGDH… potentiates tissue regeneration in multiple organs” and that “SW03329… increases prostaglandin PGE2 levels in bone marrow and other tissues” which “raise the possibility that inhibiting 15-PGDH could be a useful therapeutic strategy in several distinct clinical settings” (Abstract).
For all the foregoing reasons, Applicant’s arguments are not found persuasive. The rejection of claims is MAINTAINED.
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.
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.
Claims 31-32, 34, 38, 42-44 and 47-50 are MAINTAINED rejected under 35 U.S.C. 103(a) as being unpatentable over Shi et al (J Clin Invest 123:2064-2077, 2013; of record) and Sienkiewicz et al (Ther Adv Neurol Disord 8:166-177, published 5/18/2015; of record) in view of Mo et al (Cell Cycle 14:1507-1516, published 5/15/2015; of record) and Zhang et al (Science 348:aaa2340, published 6/12/2015; of record).
As amended, claim 31 is drawn to a method for regenerating muscle in a subject having an inherited myopathy (more specifically, wherein the inherited myopathy is Duchenne muscular dystrophy (claims 32 and 34)), the method comprising:
administering a composition comprising a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor (more specifically, a small molecule compound (claims 42-43)) to the subject in an amount effective to inhibit 15-PGDH and to activate a population of muscle stem cells in the muscle,
thereby regenerating the muscle in the subject.
As taught by Shi et al, “the maintenance and repair of adult skeletal muscle” is governed by “[m]uscle precursor cells, known as satellite cells” which “are quiescent in nature [but] respond to regenerative cues such as physical damage and exercise by undergoing cycles of proliferation” – at which point they are termed myogenic precursor cells or myoblasts – “before terminally differentiating into multinucleated myofibers” (Page 2064, Column 1). Yet, as further taught by Shi et al, “[m]yoblasts from DMD patients exhibit impaired proliferation” (Page 2064, Column 1). Significantly, Shi et al demonstrate that increasing proliferation of satellite cells and, in turn, increasing proliferation of SC-derived myoblasts, in mdx mice1 (a mouse model for Duchenne muscular dystrophy (DMD)), “enhanced skeletal muscle regeneration” (Page 2071, Column 1) and “curtailed the pathogenesis associated with DMD” (Abstract); see also Page 2069, Column 2: “SC-derived myoblasts… exhibited increased proliferative capacity”; Page 2070, Column 1: “SC-derived myoblasts… differentiated more robustly with a significantly increased level of myoblasts fusing into multinucleated myotubes”; and Page 2074, Column 1: “mdx mice [exhibiting increased proliferation of SC-derived myoblasts]… demonstrated parameters of muscle function that were equivalent of those of wild-type… mice”).
And, as taught by Sienkiewicz et al – discussing “current therapeutic methods for Duchenne muscular dystrophy” (Abstract) – treatment with granulocyte colony-stimulating factor (G-CSF) – which “induces the production of growth factors” resulting in “the proliferation of satellite cells… regulation of myoblast proliferation and differentiation, and promotion of muscle regeneration and repair” – provided “[p]ositive effects of muscle regeneration… in several studies, including… experiments on mice following muscle injuries” and “on a 15-year-old boy with facioscapulohumeral dystrophy (FSHD)” (Page 169, Column 1).
Collectively, Shi et al and Sienkiewicz et al teach methods for regenerating muscle in a subject having Duchenne muscular dystrophy, said methods comprising increasing myoblast proliferation in said subject.
However, neither Shi et al nor Sienkiewicz et al teach increasing myoblast proliferation (and, thus, regenerating muscle) by administering a composition comprising a 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor to said subject.
Yet, as taught by Mo et al, “PGE2 [prostaglandin E2] signaling… regulates myogenesis by promoting myoblast proliferation” (Abstract; see also Page 1512, Column 1: “PGE2 signaling is important for both myoblast proliferation and differentiation, the 2 critical steps for muscle development and regeneration”) and “PGE2 signaling… could have significant implications in a number of pathological disorders, such as muscle atrophy [and] muscular dystrophies” (Page 1513, Column 2).
And, as taught by Zhang et al, “a small-molecule inhibitor of 15-PGDH (SW033291)… increases prostaglandin PGE2 levels in bone marrow and other tissues” (Abstract), specifically administering 10 mg/kg SW033291 to mice by injection (Page 4).
Accordingly, in further view of Mo et al and Zhang et al, it would have been prima facie obvious to administer a therapeutically effective amount of a 15-PGDH inhibitor (such as, for example, the small molecule compound SW033291) to a subject having Duchenne muscular dystrophy in order to regenerate muscle in said subject. It would have been obvious to do so considering that Shi et al and Sienkiewicz et al teach methods for regenerating muscle in a subject having Duchenne muscular dystrophy by increasing myoblast proliferation in said subject, Mo et al teach that PGE2 signaling enhances myoblast proliferation, and Zhang et al teach that administration of a 15-PGDH inhibitor increases PGE2 levels and signaling.
And it is necessarily the case that said therapeutically effective amount of said 15-PGDH inhibitor (e.g., the equivalent of 10 mg/kg SW033291 administered to mice, based on the subject being treated) would entail “an amount effective to… activate a population of muscle stem cells in the muscle”.
As such, claims 31-32, 34 and 42-43 are rejected as prima facie obvious.
Claim 38 is drawn to the method of claim 31, wherein the composition is administered in accordance with an acute regimen – which, as defined by the Specification, embraces “e.g., single or intermittent dosing” (Paragraph 0089) including “e.g., once or twice daily… over a short period of time… e.g.,… a week” (Paragraph 0112).
As taught by Zhang et al, “mice [were] injected with SW033291” at 10 mg/kg, resulting in “a 2-fold increase in PGE2 levels”, and injection “with SW033291 at 20 mg/kg daily for 7 days” (Page 4).
As such, claim 38 is also rejected as prima facie obvious.
Claim 44 is drawn to the method of claim 31, wherein the subject is a human.
Each of Shi et al, Sienkiewicz et al, Mo et al and Zhang et al are directed to identifying treatments for muscular dystrophies such as DMD and other conditions requiring tissue regeneration (see, for example, Shi et al Abstract: identifying “a target to promote muscle stem cell function in the treatment of degenerative skeletal muscle diseases”; Sienkiewicz et al Page 167, Column 2: “searching for an effective therapy for DMD”; Mo et al Page 1513, Column 2: identifying signaling which “could have significant implications in a number of pathological disorders, such as… muscular dystrophies”; Zhang et al Abstract: “[t]issue regeneration is a therapeutic challenge during recovery from many injuries, diseases, and disease treatments), which a person of ordinary skill in the art would have understood as applying to a human subject.
As such, claim 44 is also rejected as prima facie obvious.
Claims 47-50 are drawn to the method of claim 31, wherein muscle repair is enhanced (claim 47), muscle function is enhanced (claim 48), muscle strength is increased (claim 49) and/or muscle mass is increased (claim 50).
As noted by the court in Hoffer v. Microsoft Corp. (405 F.3d 1326 (Fed. Cir. 2005)), a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited” (quoting Minton v. Nat ' l Ass ' n of Securities Dealers, Inc., 336 F.3d 1373 (Fed. Cir. 2003)).
As such, claims 47-50 are also rejected as prima facie obvious.
Claims 35, 37 and 41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Shi et al (J Clin Invest 123:2064-2077, 2013; of record) and Sienkiewicz et al (Ther Adv Neurol Disord 8:166-177, published 5/18/2015; of record) in view of Mo et al (Cell Cycle 14:1507-1516, published 5/15/2015; of record) and Zhang et al (Science 348:aaa2340, published 6/12/2015; of record) as applied to claims 31-32, 34, 38, 42-44 and 47-50 above, in further view of Markowitz et al (WO 2013/158649; of record).
Claims 35, 37 and 41 are drawn to the method of claim 31, wherein administering the 15-PGDH inhibitor comprises subcutaneous administration (claims 35 and 37) in a composition further comprising a pharmaceutically acceptable carrier (claim 41).
The teachings of Shi et al and Sienkiewicz et al in view of Mo et al and Zhang et al have been set forth above, none of which specifically teach administration as a pharmaceutical composition via subcutaneous administration further comprising a pharmaceutically acceptable carrier.
Markowitz et al teach “compositions and methods of modulating 15-PGDH activity” (Title), specifically identifying the small molecule compound SW033291 (Paragraph 0022), wherein “[a] variety of routes [of administration] are contemplated, including… subcutaneous” and wherein the composition further comprises “a pharmaceutically acceptable carrier” (Paragraph 00136).
Accordingly, in further view of Markowitz et al, it would have been prima facie obvious to administer the small molecule compound SW033291 according to the method of Shi et al and Sienkiewicz et al in view of Mo et al and Zhang et al as a composition further comprising a pharmaceutically acceptable carrier via subcutaneous administration. The simple substitution of one known method of administration for another is prima facie obvious.
As such, claims 35, 37 and 41 are also rejected as prima facie obvious.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 31-32, 34-35, 37-38, 41-44 and 47-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 9,918,994.
Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘994 claims are similarly drawn to a method for regenerating a population of muscle cells in a subject having DMD, comprising subcutaneous administration according to an acute regimen of a composition comprising a compound that inactivates or blocks 15-PGDH (claims 1-2 and 5-6).
Claims 31-32, 34-35, 37-38, 41-44 and 47-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18/704,002 in view of Shi et al (J Clin Invest 123:2064-2077, 2013; of record), Sienkiewicz et al (Ther Adv Neurol Disord 8:166-177, published 5/18/2015; of record), Mo et al (Cell Cycle 14:1507-1516, published 5/15/2015; of record) and Zhang et al (Science 348:aaa2340, published 6/12/2015; of record).
Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘002 claims are similarly drawn to a method of regenerating or rejuvenating injured, damaged, aged, or diseased tissue in a subject in need thereof, comprising administering a composition comprising a 15-PGDH inhibitor to said subject, thereby increasing the level PGE2 therein.
It would have been obvious to apply the method of the ‘002 application to the treatment of DMD in further view of Shi et al, Sienkiewicz et al, Mo et al and Zhang et al for the reasons discussed above. Namely, because it would have been obvious that application of the ‘002 method to regenerate or rejuvenate injured, damaged, aged, or diseased tissue in a subject would specifically be effective in regenerating or rejuvenating injured, damaged, aged, or diseased tissue in a subject having DMD.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any new ground(s) of rejection presented in this Office action are necessitated by Applicant’s amendments to the claims. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
1 Specifically – recognizing activation of “satellite cells to proliferate and differentiate in order to effectively repair damaged skeletal muscle” via “the mitogen-activated protein kinase (MAPK) pathway” and, in particular, “the p38 MAPK subfamily”, as “[o]ne of the more prominent signaling pathways involved in the initiation of regenerative myogenesis”, which is, conversely, inactivated by “MAPK phosphatases (MKPs)… that exhibit the capacity to dephosphorylate MAPKs… and then curtails regenerative myogenesis” (Page 2064, Column 2) – Shi et al “intercrossed Mkp5-/- mice [i.e., mice lacking the MAPK phosphatase MKP-5] into the mdx background in order generate… mdx/Mkp5-/- mice” (Page 2068, Column 2) exhibiting enhanced satellite cell and SC-derived myoblast proliferation and differentiation.