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 .
Status of Claims
Claims 1-13 are pending. The preliminary amendment filed on 12/13/2024 amended claims 7-13. There are no newly added or canceled claims.
Claims 1-13 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS/s) submitted on 8/12/2025 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Examiner’s Comment
Claims 4, 7, and 8 lack clarity and require further substantiation with regards to the phrases “wherein the disease, condition, or disorder is at an early stage of disease progression” and “wherein the disease, condition, or disorder is at a late stage of disease progression”. The specification does not explicitly define the terms “disease, condition, or disorder” specifically with reference to “aging” which is interpreted as a condition and not a disease or a disorder. Therefore, it is uncertain how aging is treated and how “an early stage of disease progression” with respect to aging and “a late stage of disease progression” with respect to aging applies to the claims.
Appropriate corrections are required.
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 9 and 10 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.
Claims 9 and 10 have limitations pointing to “one or more of muscle function, muscle structure, muscle fiber cross-sectional area, muscle regeneration, and cardiopulmonary function of the subject” and “one or more of disease progression, fibrosis, necrosis of muscle fiber, and inflammation of the subject”. Specifically, claim 9 references an improvement (i.e., “improves”), however, because the claim does not also recite a baseline or other reference point there is ambiguity as to how an improvement is assessed/determined. Similarly, claim 10 recites “ameliorates or attenuates” and also does not provide a reference point to which a comparison would be made to determine if something had been attenuated or ameliorated. Thus, it is unclear what the reference point for these comparisons is/are relative to the subject.
It is suggested that Applicant incorporate specific reference point(s) into the claim to overcome this rejection, assuming such incorporation does not introduce new matter.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-13 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 a method of treating impaired muscle regeneration comprising administering a PPARγ agonist (i.e., pioglitazone and rosiglitazone) to a very limited subset of subjects, does not reasonably provide enablement for “the disease, condition, or disorder associated with impaired muscle regeneration selected from a muscular dystrophy, an inflammatory muscle disease, trauma or injury, and aging; wherein the muscular dystrophy is selected from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Emery- Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSH or FSHD) (also known as Landouzy-Dejerine), myotonic mystrophy (MMD) (also known as Steinert's Disease oculopharyngeal muscular dystrophy (OPMD), distal muscular dystrophy (DD), and congenital muscular dystrophy (CMD); wherein the inflammatory muscle disease is selected from polymyositis, dermatomyositis, inclusion body myositis, juvenile myositis, and necrotizing autoimmune myopathy.” using “the PPARy agonist that comprises one or more thiazolidinediones.” across plethora of muscular diseases listed in claims 4-6.
Additionally, the specification does not reasonably provide enablement for particular dosage amounts, administration routes, and pharmacokinetic properties. 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.
The present specification does not enable a person of ordinary skill in the art to make and use the full scope of the claimed invention without undue experimentation for the full scope of claims 1–13.
Claim 1 broadly recites treatment of a disease, condition, or disorder associated with impaired muscle regeneration by administering a PPARγ agonist. Claim 2 further encompasses one or more thiazolidinediones. Claims 3–6 identify muscular dystrophies, inflammatory muscle diseases, trauma or injury, and aging. Claims 7–8 encompass treatment during early and late stages of disease progression. Claims 9–13 require broad therapeutic and functional results, including attenuation or amelioration of disease progression, fibrosis, muscle-fiber necrosis, inflammation, impaired muscle regeneration, muscle function, muscle structure, muscle-fiber cross-sectional area, and cardiopulmonary function.
The specification principally provides limited proof-of-concept data regarding pioglitazone in D2.mdx dystrophic mice. It does not provide commensurate evidence or guidance showing that the full claimed genus of PPARγ agonists or thiazolidinediones achieve the claimed results across the broad recited disease, stage, subject, and endpoint scope.
Accordingly, the claims are far broader than what is actually taught and reasonably predictable, particularly as to reduction in muscular disease progression across all claimed disease types.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the Invention:
The nature of the claimed invention weighs against enablement. The claims concern pharmacologic treatment of complex skeletal-muscle conditions that involve different combinations of genetic defects, muscle degeneration, immune dysregulation, chronic inflammation, fibrosis, satellite-cell dysfunction, metabolic changes, neuromuscular abnormalities, and cardiopulmonary involvement.
Claims 1–2 are directed to systemic treatment using broad classes of nuclear-receptor agonists. The efficacy of a particular PPARγ agonist or thiazolidinedione depends on compound-specific pharmacology, receptor selectivity, off-target activity, bioavailability, tissue distribution, metabolism, dose, treatment duration, and safety. The claimed therapeutic results cannot be inferred merely from classification of a compound as a PPARγ agonist.
The nature of claim 3 is complex because muscular dystrophies arise from different genetic and molecular defects. The nature of claim 4 is similarly complex because inflammatory myopathies involve variable relationships among autoimmune injury, degeneration, protein aggregation, fibrosis, and muscle-cell dysfunction. The nature of claim 5 is complex because muscle injury repair varies with injury mechanism, timing, tissue loss, inflammation, vascular compromise, and neural involvement. The nature of claim 6 is complex because aging-associated muscle impairment is multifactorial.
The prior art shows that macrophage PPARγ contributes to skeletal-muscle repair through regulation of GDF3 and effects on myoblast fusion. This supports a biological hypothesis, but it also demonstrates that the claimed effect depends on a multicellular, temporally regulated process involving immune cells and muscle progenitor cells. Such a mechanism does not make efficacy predictable across the full claim scope. (Varga, Tamas et al. “Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration.” Immunity vol. 45,5 (2016): 1038-1051.8).
The State of the Prior Art:
The state of the prior art does not provide a general, established therapeutic method for using PPARγ agonists or thiazolidinediones to treat all claimed muscle conditions. Rather, the art provides limited mechanistic and preclinical observations and demonstrates persistent uncertainty in translating muscle-regeneration findings into effective disease treatment.
As to claims 1–2, prior art recognizing PPARγ as a pharmacological target does not establish that all agonists or thiazolidinediones are effective for impaired muscle regeneration. Pioglitazone has been reported to exert anti-inflammatory effects through a PPARα-dependent mechanism in particular settings, illustrating that the effect of a drug known as a PPARγ agonist may depend on additional pathways and disease context.(Orasanu, Gabriela et al. “The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice.” Journal of the American College of Cardiology vol. 52,10 (2008): 869-81.)
As to claim 3, the state of the art recognizes that the *mdx* mouse model is useful but differs materially from human DMD. The model does not fully recapitulate the human disease, including its clinical severity and progression. The DMD literature also identifies difficulty translating promising animal-model results into clinical benefit and recognizes heterogeneity in genotype, symptoms, biomarkers, and clinical outcomes (Partridge, Terrence “The mdx mouse model as a surrogate for Duchenne muscular dystrophy. FEBS Journal vol. 280.17 (2013): 4177-86. Effects of Scale; Mouse and man grow in different ways).
As to claim 4, the prior art confirms that inflammatory myopathies are heterogeneous. Inclusion body myositis, for example, is characterized by an unresolved relationship between inflammatory and degenerative mechanisms and has remained difficult to treat effectively. The existence of a Phase I proof-of-concept pioglitazone study in inclusion body myositis demonstrates that its therapeutic use in even one listed inflammatory myopathy remained investigational (Naddaf, Elie et al. “Inclusion Body Myositis: Update on Pathogenesis and Treatment.” Neurotherapeutics: the journal of the American Society for Experimental Neurotherapeutics vol. 15,4 (2018) (Year: 2018) Abstract).
As to claim 5, the prior art regarding macrophage PPARγ and experimental muscle repair does not establish that exogenous drug administration will successfully treat each trauma or injury condition. As to claim 6, the prior art recognizes that aging-associated loss of regeneration involves varied mechanisms extending beyond macrophage-mediated signaling, including altered muscle stem-cell function and cellular senescence. (Varga, Tamas et al. “Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration.” Immunity vol. 45,5 (2016): 1038-1051.8; Page 11, paragraphs 1-3).
Thus, the prior-art state shows that the proposed therapeutic applications were not sufficiently established or predictable to supply the missing enabling disclosure.
The Relative Skill of those in the Art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The Predictability or Lack thereof in the Art:
The art is unpredictable. The claims seek therapeutic success across diverse diseases and conditions that do not share one uniform cause or disease mechanism. The relevant biological effects of PPARγ agonists are context dependent, and the claimed clinical outcomes cannot be reliably predicted from target engagement, a macrophage phenotype, or a result in a single dystrophic mouse model.
As to claims 1–2, different PPARγ agonists and thiazolidinediones may differ in receptor selectivity, potency, pharmacokinetics, metabolism, tissue distribution, and off-target effects. The specification does not establish that the claimed agents are interchangeable. The reported PPARα dependence of some pioglitazone anti-inflammatory activity demonstrates that pharmacologic effects may not arise solely from PPARγ activation and may change with biological context.(Orasanu, Gabriela et al. “The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice.” Journal of the American College of Cardiology vol. 52,10 (2008): 869-81.)
As to claim 3, efficacy in D2.mdx mice is not predictive of efficacy in all muscular dystrophies or human DMD. The *mdx* literature identifies significant translational limitations (Partridge, Terrence “The mdx mouse model as a surrogate for Duchenne muscular dystrophy. FEBS Journal vol. 280.17 (2013): 4177-86.Sections: Effects of Scale; Mouse and man grow in different ways). As to claim 4, inclusion body myositis remains refractory to available treatments despite inflammatory features, which illustrates that reducing inflammation or modulating macrophage behavior does not predict disease modification.
As to claim 5, muscle injury requires time-dependent inflammatory and reparative processes. An intervention that shifts macrophage phenotype or PPARγ signaling in one injury model may have a different or adverse effect in another injury mechanism or treatment window. As to claim 6, aging-associated impairment reflects heterogeneous, interacting biological processes, including muscle stem-cell dysfunction, fibrosis, metabolic changes, denervation, and cellular senescence.
For claims 7–13, the art is further unpredictable because the claims require specific, clinically meaningful results—attenuation or amelioration of disease progression, fibrosis, necrosis, inflammation, muscular dysfunction, and cardiopulmonary dysfunction—across all recited conditions and disease stages.
The Breadth of the Claims:
The breadth of the claims strongly weighs against enablement. Claim 1 covers any disease, condition, or disorder associated with impaired muscle regeneration and any PPARγ agonist. Claim 2 adds one or more thiazolidinediones. Claim 3 includes a broad group of muscular dystrophies. Claim 4 includes a broad group of inflammatory muscle diseases. Claim 5 includes trauma or injury without limitation as to type, mechanism, severity, timing, tissue involvement, or comorbidity. Claim 6 encompasses aging without limitation to a defined syndrome, population, mechanism, or clinical criterion.
Claims 7–8 add early and late disease stages without disease-specific definitions or objective staging criteria. Claims 9–13 add a large number of outcome limitations, each of which must be achieved throughout the full claim scope. These include improved muscle function, muscle structure, muscle-fiber cross-sectional area, muscle regeneration, and cardiopulmonary function, and attenuated or ameliorated disease progression, fibrosis, muscle-fiber necrosis, and inflammation.
The specification does not provide a commensurate number of representative examples or a unifying rule that permits reliable extrapolation to the full breadth of the agent, disease, subject, stage, and result limitations. The claims effectively require the skilled artisan to conduct a research program to determine which combinations of compounds, conditions, doses, treatment schedules, disease stages, and subjects are successful.
The heterogeneity of the claimed conditions confirms that the claim scope is not a single predictable genus. Idiopathic inflammatory myopathies are recognized as heterogeneous conditions. The biology of muscle aging is likewise heterogeneous across individuals and muscle groups. The breadth of the claims, in view of the limited and nonrepresentative disclosure, requires undue experimentation. (Titova, Angelina et al. “Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance.” Genes vol. 16,8 948. 11 Aug. 2025).
The Presence or Absence of Working Examples and Quantity of Experimentation:
The specification lacks representative working examples commensurate with the breadth of claims 1–13. The disclosed evidence principally concerns pioglitazone administered in D2.mdx dystrophic mice and is presented as proof-of-concept work. Such data do not demonstrate that the broad genus of PPARγ agonists and thiazolidinediones will achieve the recited therapeutic results across all claimed disease categories. (Titova, Angelina et al. “Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance.” Genes vol. 16,8 948. 11 Aug. 2025).
As to claims 1–2, the specification does not provide working examples for a representative range of PPARγ agonists or thiazolidinediones. There are no examples establishing comparable efficacy for rosiglitazone or other compounds within the claimed class, and no examples establishing that compound selection can be made predictably.
As to claim 3, the specification does not provide working examples in non-DMD muscular dystrophies. In particular, the disclosure lacks examples involving Becker, limb-girdle, facioscapulohumeral, myotonic, Emery-Dreifuss, congenital, oculopharyngeal, or distal muscular dystrophies.
As to claim 4, the specification contains no working examples for polymyositis, dermatomyositis, juvenile myositis, necrotizing autoimmune myopathy, or inclusion body myositis. This deficiency is significant because inclusion body myositis has both inflammatory and degenerative features and remains treatment refractory. (Naddaf, Elie et al. “Inclusion Body Myositis: Update on Pathogenesis and Treatment.” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics vol. 15,4 (2018)).
As to claim 5, the specification does not provide working examples for any distinct trauma or injury model. It does not show treatment of contusion, laceration, crush, ischemic, denervation, surgical, repetitive, or exercise-related injury. As to claim 6, it does not provide representative examples in normal non-dystrophic aging, sarcopenia, or frailty-associated impairment of muscle regeneration.
The specification also lacks working examples for claims 7–8 at both early and late disease stages and lacks representative examples demonstrating every functional endpoint required by claims 9–13, including cardiopulmonary benefit, reduced fibrosis, reduced necrosis, reduced inflammation, sustained muscle-function improvement, and attenuation or amelioration of disease progression.
The known limitations of the *mdx* mouse reinforce the lack of representative examples. The literature recognizes material differences between the *mdx* model and human DMD with respect to pathology, clinical severity, disease progression, and translational outcome measures.
Furthermore, the quantity of experimentation needed to practice claims 1–13 across their full scope is extensive and undue. For each candidate PPARγ agonist or thiazolidinedione encompassed by claims 1–2, a skilled artisan would need to determine target engagement, pharmacokinetics, skeletal-muscle exposure, toxicity, dose, route, frequency, treatment duration, and whether the agent produces the claimed result. The specification does not supply a predictive structure-activity relationship, screening method, target-engagement threshold, or efficacy criterion permitting a skilled artisan to identify effective compounds without empirical testing.
As to claim 3, a skilled artisan would need to separately test the claimed agents in multiple muscular dystrophies. The scope includes dystrophinopathies, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, and distal muscular dystrophy. These conditions have distinct genetic causes and clinical manifestations. The disclosed D2.mdx dystrophinopathy model cannot eliminate the need for separate studies in the remaining disorders.
This level of trial-and-error analysis, across many disease etiologies, goes well beyond routine optimization and constitutes undue experimentation.
Note that lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164. Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
Therefore, in view of the Wands factors, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 1-13.
Consequently, 1-13 are rejected for lacking scope of enablement.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-13 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Ng et al., (“METHODS AND COMPOSITIONS FOR TISSUE REGENERATION”, Pub. No.: WO 2021/052370 A1; Pub. Date: March 25, 2021), herein referred to as Ng.
Regarding claims 1-13, Ng discloses methods of treating a disease or condition associated with muscle tissue by administering an effective amount of a pharmaceutical composition comprising a fatty-acid-oxidation activator. The reference expressly identifies a PPARγ agonist as an FAO activator and expressly identifies rosiglitazone as a PPARγ agonist [0035-0039]. Ng further discloses that the tissue may be muscle tissue and that the disease or condition may be muscle injury, muscle degeneration, aging, inflammatory myopathies, or muscular dystrophy [0172, 0289].
Furthermore, Ng additionally provides an in-vivo embodiment in which mice undergo cryoinjury of the tibialis anterior muscle followed by intramuscular administration of the PPARγ agonist rosiglitazone [0468-0469]. The reference reports increased expression of myogenic differentiation markers and confirms that rosiglitazone administration improved skeletal-muscle regeneration in vivo [0309]. Accordingly, Ng discloses each limitation of claim 1, including administration of a PPARγ agonist to a subject for treatment of a condition involving impaired muscle regeneration. It teaches PPARγ agonist, thiazolidinediones, rosiglitazone and in some embodiments according to any one of the methods described above, the one or more FAO activators or activators of PPARγ comprises a PPARγ agonist. In some embodiments, the PPARγ agonist is a thiazolidinedione or derivative thereof, or a salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the PPARγ agonist is a compound of Formula (I) [0031, 0379]
Conclusion
Claims 1-13 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHAR INAM whose telephone number is (571)272-0821. The examiner can normally be reached 7:30 am-5:00 pm EST.
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/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/
Supervisory Patent Examiner, Art Unit 1622
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