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 Application, Amendments and/or Claims
The amendment, filed 22 February 2024, has been entered in full. Claims 1, 24, 25 are canceled. Claims 2-23, 26-29, 33-36 and 38 are amended.
Applicant’s election without traverse of Group I (claims 2-23, 26, 33-38 drawn to a method for treating at least one symptom of an ACVR1-associated disease or disorder comprising administering an antibody to a subject) and the species election (mutant ACVR1 R206H protein, the species of CDRs SEQ ID NO: 44-46-28-50-52-36 of representative mAb 27242 and SEQ ID Nos: 24-46-60-50-64-66 of representative mAb 27243; the species of HCVR/LCVR pair of SEQ ID NO: 42/48 of representative mAb 27242 and SEQ ID NO: 58/62 of representative mAb 27243), in the reply filed on 03 February 2026 is acknowledged.
Claims 27-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03 February 2026.
The amendment, filed 03 February 2026, has been entered in full. Claims 9, 10, 15-23, 27-32 are canceled. Claims 8, 11-14, 26 and 33 are amended.
Claims 2-8, 11-14, 26, 33-38 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 2/22/2024 and 11/4/2025) were received and comply with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. They have been placed in the application file and the information referred to therein has been considered as to the merits.
Claim Objections
Claim 33 is objected to because of the following informalities:
“..a ACVR1-associated disease or disorder..” should be “..an ACVR1-associated disease or disorder..”. Appropriate correction is required.
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.
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 2-8, 11-14, 26, 33-38 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 instant claims are indefinite for the following reasons:
1. Claims 11, 13 and 33 are indefinite because of the recitation, “..an amino acid sequence..”. The word “an” is regarded as meaning "one". Thus, it is not clear if the claims read on peptide fragments (such as having one or two amino acid residues) or comprising the recited SEQ ID NO: sequence.
Amending the claims to recite, “..the amino acid sequence..”, would be remedial.
Claims 2-8, 12, 14, 26, 34-38 are included in this rejection insofar as they depend from claim 33 and do not resolve the issue discussed above.
2. Regarding claim 8:
2a. The phrases "(e.g., SEQ ID NO: 339)", "(e.g., SEQ ID NO: 338)", "(e.g., SEQ ID NO: 340)" render the claim indefinite because it is unclear whether the limitations following in phrase are part of the claimed invention. See MPEP § 2173.05(d).
2b. The recitation of “Fc” and “mFc” renders the claim indefinite. Claim 8 recites “Fc” and “mFc” as both having the same sequence (i.e. SEQ ID NO: 339), but it is unclear how “Fc” differs from “mFc”. The instant specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
2c. The recitation “significantly decreases” (claim 8n) and “significantly increases” (claim 8o) renders the claim indefinite. The limitation “significantly” is a subjective term and the specification does not provide a standard for measuring the scope of the term (see MPEP 2173.05(b)(IV)).
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 2-8, 11-14, 26, 33-38 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 or ameliorating at least one symptom or indication of an ACVR1-associated disease or disorder wherein said ACVR1-associated disease or disorder is heterotopic ossification, ectopic ossification or optionally wherein the heterotopic ossification is post-traumatic heterotopic ossification, wherein said treating or ameliorating decreases the formation of new heterotopic ossification or new ectopic ossification, the method comprising...”
“A method of treating or ameliorating at least one symptom or indication of an ACVR1-associated disease or disorder wherein said ACVR1-associated disease or disorder is anemia, wherein said treating or ameliorating decreases serum hepcidin and increases serum iron levels, the method comprising...”
does not reasonably provide enablement for:
“A method of treating, preventing or ameliorating at least one symptom or indication of an ACVR1-associated disease or disorder...”
“A method of treating, preventing or ameliorating at least one symptom or indication of an ACVR1-associated disease or disorder wherein the ACVR1-associated disease or disorder is selected from the group consisting of bone dysplasia and diffuse intrinsic pontine glioma…”
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The Examples employ an animal mouse model wherein BMP6 mediated activation of ACVR1 directly activates transcription of the gene that encodes hepcidin. Hepcidin is a negative regulator of iron levels by causing internalization of ferroportin. The Examples teach that inhibition of the BMP6-ACVR1 signaling cascade leads to decreased Hamp transcription, resulting in decreased circulating levels of hepcidin. A reduction of circulating hepcidin results in increased ferroportin levels, which allows increased uptake of iron from the small intestines, thereby increasing circulating iron levels. The Examples teach administering the claimed antibody decreases serum hepcidin and increases serum iron levels in the mouse model (paras 0214-0218).
The Examples employ an animal mouse model of in vivo post-traumatic heterotopic ossification (HO). The Examples teach heterotopic ossification (HO), the formation of ectopic bone in soft tissues, occurs in two primary forms: post-traumatic HO (tHO) typically found in patients who have experienced musculoskeletal or neurogenic injury and the genetically driven fibrodysplasia ossificans progressive (FOP) downstream to a specific point mutation known as R206H in the ACVR1 receptor. The Examples teach both diseases undergo a process of endochondral ossification in the formation of ectopic bone. The Examples teach administering the claimed antibody attenuated HO in the post-traumatic HO mouse model (paras 0219-0227, 0230-0231).
The specification is not enabled for the full breadth for the following reasons:
1. The instant claims recite the limitation “preventing”. “Preventing" is an all-or-nothing term; it means to completely stop something from occurring. “Prevention” is not a relative term, it is total. A very high degree of evidence is required, which is accepted in the art, that an absolute protection from the pathology exists over an extended period of time. It could not be predicted that administering the claimed ACVR1 antibody or antigen-binding fragment thereof would completely stop a symptom or indication of an ACVR1-associated disease or disorder from ever occurring.
2. The instant claims recite the limitation “ACVR1-associated disease or disorder”. The specification teaches heterotopic ossification, ectopic ossification, bone dysplasia, anemia, and diffuse intrinsic pontine glioma, optionally wherein the heterotopic ossification is post-traumatic heterotopic ossification, as examples of ACVR1-associated diseases or disorders.
However, an “ACVR1-associated disease or disorder” can encompass other very diverse diseases and disorders. The specification and the references of record fail to teach any correlation between for example, “ectopic ossification” and any other ACVR1-associated disease or disorder, wherein the skilled artisan could use the claimed method. There is substantial variation among “ACVR1-associated diseases or disorders”. There is no information regarding what features would likely be associated with such diseases/disorders.
The recitation of heterotopic ossification, ectopic ossification, bone dysplasia, anemia, and diffuse intrinsic pontine glioma, optionally wherein the heterotopic ossification is post-traumatic heterotopic ossification is not tantamount to the full breadth of treating or ameliorating a symptom or indication of all “ACVR1-associated diseases or disorders”.
3. The instant claims recite the limitation “treating or ameliorating at least one symptom or indication of an ACVR1-associated disease or disorder”.
The specification fails to teach a particular symptom or indication of any purported “ACVR1-associated disease or disorder”. Therefore, it is unclear how to use this method. The skilled artisan would need to know the particular “ACVR1-associated disease or disorder” AND would need to know the particular symptom or indication that is being treated or ameliorated.
4. The specification is not enabled for treating or ameliorating any symptom or indication of Diffuse Intrinsic Pontine Glioma (DIPG) or bone dysplasia.
Regarding Diffuse Intrinsic Pontine Glioma (DIPG), Weisbrod et al. teach DIPG as a childhood malignancy of the brainstem with a dismal prognosis and that despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. Weisbrod et al. teach that the median survival of DIPG is less than 1 year, and the overall survival is less than 1 % at 5 years (page 1). Weisbrod et al. teach that the pontine location of DIPGs within the brainstem restricts maximal safe resection and is not a feasible treatment option and that the current standard treatment regimen is temozolomide with concurrent external beam radiotherapy. Weisbrod et al. teach that any otherwise promising pharmaceuticals for CNS disorders have failed to achieve clinical success due to an intact blood-brain barrier (BBB). Delivery to the brain may be increased with higher doses of systemic administration but at the expense of increased side effects and system toxicity (page 4). Weisbrod et al. teach that animal models constitute a valuable tool in studying DIPG and are the key to uncovering novel therapeutic vulnerabilities. Weisbrod et al. teach that given DIPG’s rare occurrence and its eloquent location within the brainstem, obtaining DIPG tissue has been difficult and ultimately restricted prior research efforts (page 6)(Weisbrod et al. Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies. Cancer Letters 590 (2024) 216876, 13 pages; 2024).
Regarding skeletal (bone) dysplasia, Francomano et al. teach skeletal dysplasias are a heterogeneous group of disorders. Francomano et al. teach gene mutations and genotype-phenotype such as COL1A1, which causes Osteogenesis imperfecta types I-IV and Ehlers-Danlos syndrome type VII; COL1A2 which causes Osteogenesis Imperfecta types I-IV and Ehlers-Danlos syndrome type VII; COL3A1 which causes Ehlers-Danlos syndrome type IV; COL5A1 which causes Ehlers-Danlos syndrome type II; COL2A1 which causes Achondrogenesis type II, hypochondroplasia, Kniest dysplasia, Spondyloepi (meta)physeal dysplasia, Stickler syndrome and osteoarthritis with mild SED; COL9A2 which causes Multiple epiphyseal dysplasia; COMP which causes Pseudoachondroplasia and multiple epiphyseal dysplasia; FGFR3 which causes Acromesomelic chondrodysplasia (Hunter-Thompson type), Achondroplasia, Thanatophoric dysplasia (types 1 and 2), Hypochondroplasia and Crouzon syndrome with Acanthosis-Nigricans; and FGFR2 which causes Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome and Pfeiffer syndrome (Table 1)(Francomano et al. Bone dysplasias in man: molecular insights. Current Opinion in Genetics & Development 6:301-308; 1996).
Given the guidance of the specification, one of ordinary skill in the art could reasonably predict that administration of the claimed antibody would be useful in methods of treating symptoms/indications involving heterotopic and ectopic ossification or serum hepcidin and serum iron levels. However, the specification and the submitted references fail to teach that the employed animal models would be predictive of treatment of symptoms/indications of diffuse intrinsic pontine glioma (DIPG) or treatment of symptoms/indications of the heterogeneous group of bone dysplasia. It could not be predicted the affects the administered claimed antibody would have in a subject with DIPG or bone dysplasia.
See wherein Justice et al. state, “It seems an obvious point, but the model used should be appropriate for the question being addresses. An ideal disease model accurately mimics the human condition, genetically, experimentally and/or physically”. Justice et al. teach that in one example, data from human blunt-trauma patients were analyzed together with data from a mouse inbreed strain that had been exsanguinated. Justice et al. teach, “Losing a large amount of blood does not equate to blunt trauma, and so this could be perceived as comparing apples to oranges” (page 101, 2nd column 2nd full paragraph). Justice et al. teach that in a different study, a mouse model was reported to display the key motor symptoms seen in humans with amyotrophic lateral sclerosis (ALD). On the basis of this, the model was used in preclinical trial studies and promising drugs candidates were tested in clinical trials; however, the drugs ultimately failed in humans. It was show that the particular mouse is a poor genetic and phenotypic model of human conditions. Justice et al. state, “This example illustrates how relevance to the human disease being studied, supported by strong data to validate the use of the model is crucial for clinical translation” (page 102, left column, 1st full paragraph)(Justice et al. Using the mouse to model human disease: increasing validity and reproducibility, Disease, Models & Mechanisms 9:101-103, 2016).
Due to the inherent unpredictability and the large quantity of experimentation necessary to show that the onset of a symptom or indication of an ACVR1-associated disease or disorder has been prevented; the inherent unpredictability and the large quantity of experimentation necessary to treat or ameliorate any symptom or indication of all ACVR1-associated disease or disorder; the lack of direction/guidance presented in the specification, the absence of working examples; the complex nature of the invention; the state of the art which establishes the use of proper animal models; and the breadth of the claims which fail to recite proper limitations regarding specific symptoms and indications which can be treated or ameliorated in particular ACVR1-assocated disease or disorder, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Closet Prior Art
Kaplan et al. teach a method for treating heterotopic and ectopic ossification comprising administering a siRNA made against a nucleic acid encoding a mutated Activin A type I receptor (ACVR1) or administering a siRNA against a nucleic acid encoding a mutated ACVR1 in combination with an anti-ACVR1 antibody (Kaplan et al. US 8,895,711; published Nov. 25, 2014).
Warner et al. teach a method for treating anemia comprising administering N.sup.4-(2,2′-bipyridin-3-yl)-N.sup.2-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine or administering N.sup.4-(2,2′-bipyridin-3-yl)-N.sup.2-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine in combination with an anti-ACVR1 antibody (Warner et al. US 11,040,038; published June 21, 2021, priority date July 26, 2018).
None of the references teach an anti-ACVR1 antibody comprising the amino acid sequences of complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCD3, as recited in the instant claims.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 3/18/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647