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 .
Response to Amendment
Applicant’s response filed 14 July 2025 has been received and entered. Claims 1, 8-10, 12, 14, 20-23 and 26 are currently amended, claims 2, 5-7, 15-18 and 25 have been canceled and claims 27-28 have been newly added in the amendment filed 14 July 2025. Claims 1, 3-4, 8-14, 19-24 and 26-28 are currently pending and under consideration in the instant Office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action has been overcome by Applicant's response and withdrawn.
Applicant's arguments filed 14 July 2025 have been fully considered but are not found to be persuasive.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 14 July 2025 has been considered by the examiner.
Drawings
The drawings were received on 14 July 2025. These drawings are unacceptable for the same reasons provided in the previous Office action (mailed 14 March 2025)..
The drawings are objected to because they do not comply with 37 CFR 1.84.
37 CFR 1.84(a)(1) states that black and white drawings must use India ink, “or its equivalent that secures solid black lines.”
37 CFR 1.84(b) (1) states that photographs are not ordinarily permitted in utility applications but that the Office will accept photographs if they are the only practicable medium for illustrating the claimed invention. However, the “photographs must be of sufficient quality so that all details in the photographs are reproducible in the printed patent”. Figures 2B, 2D, 2F, 6B and 6D include photographs, however, they are not of sufficient quality to identify the details which the photographs are to be demonstrating.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to Arguments
Applicant indicates that new drawings were filed. While the submission is present in the instant application, the drawings appear to be identical to those submitted with the filing of the instant application. The objection to the drawings is maintained for the reasons of record.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicant’s submission of a substitute specification correcting the incorporation statement has been received and entered. The instant application is now in sequence compliance.
Specification
The abstract of the disclosure is objected to because it contains speculative applications (i.e. prevention). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The disclosure remains objected to because of the following informalities: the chemical structures appearing on page 37 of the specification (paragraph [0123] are not clear and do not comply with 37 CFR 1.52(a)(1)(iv-v) which requires permanent dark ink or its equivalent and sufficient clarity and contrast between the paper and writing thereon to permit direct reproduction of readily legible copies in any number by use of photographic, electrostatic, photo-offset, and microfilming processes and electronic capture by use of digital imaging and optical character recognition (see below).
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The chemical structures are not clear, are not in dark ink or its equivalent and not of sufficient clarity to permit direct reproduction of readily legible copies. Appropriate correction is required.
Response to Arguments
Applicant asserts at page 13 of the response that the chemical structure images on page 37 (paragraph [0123]) have been replaced with higher-contrast figures.
Applicant’s assertion is noted but no difference in clarity was achieved by the “higher contrast figures”. The screenshot provided above is from the latest filing of 14 July 2025. When the images are magnified, it is clear that the text and lines of the structures are not solid, which results in the fuzzy, gray appearance. Therefore, the objection is maintained for the reasons of record.
Claim Objections
Claim 1 and dependent claims are objected to because of the following informalities:
Claim 1 has been amended to recite “an activin receptor type II (ActRII) antibody, or a fragment thereof which retains ActRII binding specificity, comprising the three heavy chain CDRs of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and the three light chain CDRs of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6”. The recitation of binding specificity was added to avoid issues with the previous recitation of “functional”.
While this amendment addresses the previous issue with the term “functional”, it has introduced grammatical issues in the dependent claims when referring to the antibody and fragment which is recited in claim 1. The fragment in claim 1 is not a species, but rather, it is a genus as it encompasses any “fragment” which retains binding specificity and comprises all 6 CDRs. However, in attempting to provide proper antecedent basis, the dependent claims all refer to “the fragment thereof” which is actually not correct as there is no singular fragment recited in claim 1 (“a” is an indefinite article and “the” is a definite article).
The following language for claim 1 is suggested in order to more clearly define what is claimed and to make reference back to the elements of claim 1 easier:
“… an activin receptor type II (ActRII) antibody, or binding-fragment thereof, wherein the antibody or binding-fragment thereof comprise heavy chain CDRs having the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and light chain CDRs having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6”.
Dependent claims can then refer back to claim 1 and recite “the activin receptor type II (ActRII) antibody, or binding-fragment thereof”.
Claim 27 is objected to because of the following informalities:
Claim 27, element (h) recites “the pyruvate synthase inhibitors is”. As only one compound is recited, inhibitor should be singular and not plural.
Claim 27 includes two elements labeled (j); one is “the Acetyl-CoA carboxylase inhibitor and the other is “the FXR agonist”.
Claim 27 recites “the FXR agonist” as element (a) and as element (j). As the options for each are all FXR agonists, it is suggested that they all be listed together under element (a). If they are listed separately because the options in (a) and those listed in (j) are in some way different, some sort of distinction should be made with regard to “FXR agonist”.
Claim 27 recites elements (a)-(n) in the alternative using the term “or”. This seems to be an error. As claim 27 is reciting the alternatives for each of the generic compounds to be administered, the collection of alternatives for each generic compound is not in the alternative. Meaning, the method of claim 26 is not limited to only (a) or to only (n); which is implied by the use of “or” at the end of element (m). It is suggested that “or” be replace with “and”.
Appropriate correction is required.
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.
Claim(s) 1, 3-4, 8-10, 19-23 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2011/056896 (Koncarevic et al.) in view of US Pat. Pub. 2010/272734 (Berger et al.) and WO2018/116201 (Garito et al).
Koncarevic et al. disclose the use of antagonists of the ActRIIB signaling pathway for the treatment of fatty liver disease, hepatic steatosis, NAFLD, NASH and hepatic fibrosis (see page 2, lines 3-24, page 4, line 28 – page 5, line 22, and claims 1-27) as well as related disorders such as insulin resistance or hyperinsulinemia (bottom of page 4). Koncarevic et al. disclose that the ActRIIB antagonist may be a compound that inhibits ActRIIB signaling pathway by targeting ActRIIB (see page 5, line 25) or an antagonist that binds to ActRIIB wherein the antagonist is an antibody that binds ActRIIB (see claims 19-21). Koncarevic et al. teach that therapeutic compositions can be administered in any convenient way and include topically, systemically or locally (see page 36 under “Pharmaceutical Compositions”) which would necessarily encompass intravenous administration as well as subcutaneous administration. Koncarevic et al. disclose and reduce to practice treatment of hepatic steatosis in a mouse model of diet-induced obesity by administration of an inhibitor of ActRIIB wherein the inhibitor is a truncated ActRIIB-Fc fusion (see Example 3). The administration of the ActRIIB inhibitor almost completely prevented hepatic lipid deposition despite the high-fat diet. Koncarevic et al. does not administer an ActRIIB antibody or an antibody comprising the amino acid sequences of SEQ ID NO:1-6 of claim 1.
US Pat. Pub. 2010/272734 (Berger et al.) discloses anti-ActRIIB antibodies (see [0008]-[0012]) for use in the treatment of liver disease including liver fibrosis and cirrhosis and hepatocellular carcinoma (see [0027] and claims 37-38, 40-41 and 43). Berger et al. also disclose that anti-ActRIIB antibodies can be used to treat metabolic disorders including Type II Diabetes and metabolic syndrome (see [0026]). Berger et al. do not teach the treatment of a liver disease/disorder with the ActRII antibody comprising the amino acid sequences of SEQ ID NO:1-6.
WO2018/116201 (Garito et al.) disclose an antibody to ActRII, named bimagrumab (BYM338) which antagonizes ActRII. Garito et al. disclose that bimagrumab comprises the amino acid sequences of SEQ ID NO:1-6 (the 6 CDRs from the heavy and light chains of the antibody) (see page 13, lines 1-15). These amino acid sequences are identical to those of SEQ ID NO:1-6 of the instant claims. While Garito et al. did not investigate treatment of liver disease, Garito et al. does teach administration of bimagrumab at a dose of 10 mg/kg and wherein the antibody is administered monthly for up to a year (see page 26, lines 20-26). Garito et al. additionally teaches therapeutic agents for treating type 2 diabetes beginning at page 39 of the disclosure.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Koncarevic et al. of treating liver diseases/disorders such as fatty liver disease, hepatic steatosis, NAFLD, NASH and hepatic fibrosis by administering an antibody which binds ActRII because Koncarevic et al. teach the use of antagonists of the ActRIIB signaling pathway and because Berger et al. discloses treatment of liver disease by administering anti-ActRIIB antibodies. Furthermore, it would have been obvious to administer the antibody of Garito et al. which comprises the amino acid sequences of SEQ ID NO:1-6 (named bimagrumab) because Garito et al. teaches that the antibody antagonizes ActRII and because Garito et al. teaches that the antibody is safe to use in subjects.
While the combination of references do not specifically state that effectiveness of the treatment is assessed using the NAFLD Activity Score (NAS) as recited in claims 9-10, this scoring system is well-known in the art to which the invention is directed and those in the art would understand that assessment of the severity and activity of NAFLD can be reported using this scoring system based on fat accumulation, inflammation and swelling and is scored on a scale of 0-3. Therefore, practicing the method of Koncarevic et al. using the antibody of Garito et al. wherein the subject reduces the NAS of the subject by at least 1 point would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention because a reduction in the NAS would indicate that the treatment is effective.
With regard to claims 20-23, Garito et al. does teach administration of bimagrumab at a dose of 10 mg/kg and wherein the antibody is administered monthly for up to a year (see page 26, lines 20-26). While Garito et al. does not administer bimagrumab for the treatment of liver disease, Garito et al. does teach that this dose and regimen of bimagrumab is safe and is effective to produce physiological results for treating obesity and type 2 diabetes and for increasing insulin sensitivity. It would have been obvious to one of ordinary skill in the art before the effective filing date to determine an optimal dosage and dosing regimen and further, one would be motivated to use the dosages and dosing schedule utilized by Garito et al. because it was found to be safe and effective for treating a comorbidity of NAFLD. One would have had a reasonable expectation of success because Berger et al. already teach that ActRII antibodies can be used to treat liver disease and Garito et al. teach dosages of bimagrumab, an ActRII antibody, which can be administered to a subject for therapeutic effects.
Response to Arguments
Applicant argues at page 15 of the response that Koncarevic et al. is a “non-enabling reference as it discloses no specific reference to any antibody or any structural or functional properties that such an antibody would need to have, nor does it enable such an antibody in any manner” (emphasis omitted).
Applicant’s argument has been fully considered but is not persuasive. Koncarevic et al. was cited for the teaching of the use of antagonists of the ActRIIB signaling pathway for the treatment of fatty liver disease, hepatic steatosis, NAFLD, NASH and hepatic fibrosis as well as related disorders such as insulin resistance or hyperinsulinemia. While Koncarevic et al. did not reduce to practice an antibody which binds and inhibits ActRIIB, Koncarevic et al. clearly indicate the functionality necessary for practicing the disclosed methods of treatment as the method of Koncarevic et al. is achieved by administration of antagonists of the ActRIIB signaling pathway. Therefore, the antibodies which are contemplated by Koncarevic et al. bind ActRIIB and are antagonistic.
Applicant asserts that Koncarevic et al. describes a soluble ActRIIB polypeptide antagonist in their disclosed method, wherein the soluble receptor binds the ligands which would normally bind the receptor, thus preventing them from binding their natural receptors. Applicant also asserts that the soluble ActRIIB antagonist of Koncarevic et al. would also prevent the ligands from binding to other receptors, such as BMPR2. Applicant asserts that “the invention of these ligands collectively is unlikely to result in the same effect as when they are inhibited selectively, as with the antibodies claimed herein”.
Applicant’s argument has been fully considered, but is not found persuasive. While the effect achieved by administration of a soluble ActRIIB antagonist may not be identical to that of an antibody which antagonizes ActRIIB, one of ordinary skill in the art would still reasonably expect that blocking ActRIIB would result in the treatment of NAFLD, NASH or liver fibrosis because Koncarevic et al. clearly disclose that fatty liver disease can be treated by using antagonists of the ActRIIB signaling pathway. Additionally, the prior art before the effective filing date of the claimed invention was clearly aware of the role that ActRIIB ligands played in the pathogenesis of liver disease as evidenced by Applicant’s IDS submissions. For example, Yndestad et al. (Am J. Gastroenterol. 2009; 104:2196-2205) clearly establish that activin A is linked to hepatic fibrosis (see page 2203, column 2), WO 2013/063536 teaches that liver fibrosis can be treated with anti-ActRIIB antibodies (see paragraph spanning pages 4-5 and claim 22) and WO2017/156488 teaches antibodies which bind ActRII and that these antibodies can be used to treat fibrotic conditions (see [0006]) including hepatic fibrosis (see [0041] and [0047]). Therefore, one of ordinary skill in the art would have a reasonable expectation that anti-ActRIIB antibodies would be useful for the treatment of fatty liver disease, hepatic steatosis, NAFLD, NASH and hepatic fibrosis as taught by Koncarevic et al.
Applicant argues at page 16 of the response that Koncarevic provides no guidance as to the specific mechanism by which the soluble ActRIIB polypeptide achieves its therapeutic effect. Applicant asserts that because the soluble ActRIIB polypeptide binds multiple ligands, this “broad ligand neutralization can result in unpredictable dose-response outcomes leading to safety risks and thus serves as a less desirable therapeutic mechanism of action when compared to a highly specific antibody, such as the antibodies claimed therein”. Applicant then concludes “a person skilled in the art would not have considered the use of an antibody, and certainly not the antibodies such as those claimed herein, as a ActRIIB antagonist as described in Koncarevic with any reasonable expectation of success”.
Applicant’s arguments have been fully considered but are not found persuasive. First, there is no requirement that Koncarevic provide a mechanism by which soluble ActRIIB achieves its therapeutic effect. However, Koncarevic clearly teaches the mechanism by which the antagonists operate is by antagonizing the ActRIIB signaling pathway. The soluble receptor binds up the ligands which bind ActRIIB and thereby prevent them from inducing signaling while an antibody which binds ActRIIB would block ligands from binding the receptor and therefore, prevent signaling. Next, Applicant’s arguments regarding using a “highly specific antibody” are not convincing as a lack of motivation or a lack of reasonable expectation of success of practicing the method of Koncarevic with an anti-ActRIIB antibody, but rather, the arguments seem to favor the use of an anti-ActRIIB antibody over the soluble receptor which was reduced to practice by Koncarevic.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues at page 16 of the response that Berger is “merely directed to the development and use of exemplary ActRII antibodies in treatments requiring increased skeletal muscle weight” and that Berger makes mention of the treatment of liver fibrosis or cirrhosis in the context of a number of other unrelated pathological disorders.
Applicant’s argument has been fully considered, but is not found persuasive. Paragraph [0030] clearly indicates why Berger discloses that liver fibrosis and cirrhosis can be treated with the anti-ActRIIB antibodies which are exemplified. While at first glance, the various pathological disorders may appear to be unrelated, Berger provides the relationship which is the ActRIIB receptor.
In the paragraph spanning pages 16-17, Applicant argues that Garito does not cure the deficiencies of either Koncarevic or Berger and asserts “the use of the antibodies claimed herein result in unexpected clinically relevant properties”. Applicant argues that Garito does not teach or suggest any effect on hepatic fat. Applicant references paragraph [0183] for the assertion of an unexpected result. Applicant’s argument has been fully considered, but is not found persuasive. For a result to be unexpected, it needs to be compared to the closest prior art. The result which is described in paragraph [0183] compares bimagrumab administration with placebo, however, placebo would not be considered the closest prior art.
Claim(s) 1, 11-14, 24 and 26-28 are is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2011/056896 (Koncarevic et al.) in view of US Pat. Pub. 2010/272734 (Berger et al.) and WO2018/116201 (Garito et al.) and further in view of Glass et al. (Fed. Pract. 36(2): 64-71, Feb. 2019).
The disclosures of Koncarevic et al., Berger et al., and Garito et al. area as provided above. None of these cited references teaches the treatment of liver disease in a subject who is also diabetic, obese, or has metabolic syndrome.
Glass et al. teach that nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of severity from steatosis and nonalcoholic steatohepatitis steatosis (NASH). NAFLD is significantly associated with metabolic syndrome (which is a cluster of conditions including abdominal obesity, high blood pressure, impaired fasting blood glucose, high triglyceride levels and low HDL). Figure 2 of Glass et al. show that NAFLD comorbidities include obesity, type 2 diabetes and metabolic syndrome more than 50% of the time.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Koncarevic et al. to treat liver disease with the antibody of Garito et al. based on the teaching of Berger et al. in a subject who was also diabetic or obese or who also had metabolic syndrome because Glass et al. teach that such conditions are comorbidities with NAFLD. It would have been obvious to select a subject who was already receiving standard care for the treatment of type 2 diabetes because a subject having such a condition would normally be treated for the condition. With regard to claim 14, the standard of care treatment for type 2 diabetes is old and well-known in the art. As Glass et al. teach that subjects suffering from NAFLD more likely than not also suffer from type 2 diabetes, treating a subject having both NAFLD and type 2 diabetes would have been obvious, absent evidence to the contrary.
Response to Arguments
Applicant argues at page 17 of the response that Glass merely describes the statistical co-occurrence of NAFLD with metabolic syndrome, obesity and type 2 diabetes but provides no teaching or suggestion that treatment of NAFLD with an anti-ActRII antibody could treat these comorbidities.
Again, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The instant claims are not directed to treatment of diabetes, obesity or metabolic syndrome nor do any of the instant claims recite treatment of these conditions with an ActRII antibody. Claim 1 is a method of treatment of NAFLD, NASH or liver fibrosis in a subject in need thereof. Claim 22 which depends from claim 1 recites that the subject is a diabetic subject, an obese subject or a subject with metabolic syndrome or another metabolic disorder. Therefore, what the claim encompasses is a subject that is in need of treatment for NAFLD, NASH or liver fibrosis and who also suffers from diabetes, obesity, metabolic syndrome or a metabolic disorder. Therefore, the teachings of Glass are relevant because Glass et al. teach that such conditions are comorbidities with NAFLD.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 6am-2:30pm.
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/Christine J Saoud/Primary Examiner, Art Unit 1645