DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/02/2026 has been entered.
Claim Status
Claims 1-37 are cancelled. Claims 38-46 as filed on 02 April 2026 are pending and under examination.
Rejections Withdrawn
Rejection of claims 38-46 under 35 U.S.C. 112(b) is withdrawn with applicant amendment to claims.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 38-46 are rejected under 35 U.S.C. 103 as being unpatentable over Nanchachal (WO 2012/056044 A1) (Of Record), Theiss et al (J. Biol. Chem., 2005, 280(43):36099-36109) (IDS), Verjee et al (Proc. Natl. Acad. Sci. USA, 2013, 110(10):E928-E937) (IDS), and Faustman (WO2014/124134) (Of Record).
Regarding claim 38-39, Nanchachal teaches a method of treating fibroproliferative disorders including Dupuytren’s disease with a TNF-α antagonist (abstract and claims 1-3). Nanchachal teaches the method of the claims includes any TNF-α antagonist includes an antibody (page 17 in lines 5-8) Nanchachal teaches the treatment of early form of the disease (claim 5), and established disease (page 13 in lines 20-25). Nanchachal teaches a proposed mechanism for pathogenesis in Dupuytren’s disease that acts via TNFα binding TNFR teaching binding to TNFR as playing a role in Dupuytren’s disease (Figure 19).
Regarding claim 40, Nanchachal teaches bi-functional antibodies (page 17 in lines 17-30).
Regarding claims 41-42 and 46, Nanchahal teaches that TNFα inhibitors can be injected for treatment of Dupuytren’s disease (claims 12 and 32). Nanchachal teaches TNFα inhibitors can be administered at 1 to 100 mg or 5 to 50 mg or 10 to 40 mg by injection into nodules (page 12 in lines 21-31). Nanchahal teaches that clinical nodules are subcutaneous lumps so injections into nodules would be subcutaneous (page 20 in lines 8-9).
Regarding claim 43, Nanchahal teaches that TNFα inhibitors the administration daily (page 22 in lines 29-31).
Nanchachal teaches the treatment of multiple fibrosis diseases including Dupuytren’s disease via an antagonist of TNFα either alone or in combination with DAMP and/or AGE inhibitors directly to the site of fibrosis.
Nanchachal does not teach the use of an anti-TNFR2 antibody in its method.
These deficiencies are filled by Theiss, Verjee, and Faustman.
Theiss teaches that TNFα stimulation resulted in increased collagen accumulation (Fig. 1) in myofibroblasts via a mechanism which involves inhibition of collagen degradation (Fig. 2). TNFα-mediated collagen accumulation was absent in TNFR2-deficient, but did occur in wild-type and TNFR1-deficient cells (Fig. 3 and Fig. 4; p. 36105, 2nd column, last paragraph – p. 36106, 1st column, 1st paragraph). Theiss concludes that TNFR2 is a primary mediator of fibrogenic actions of TNFα by promoting collagen accumulation via inhibition of collagen degradation (see abstract; p. 36108, 1st column, last paragraph – p. 36109, 1st column).
Verjee teaches that TNF signaling promotes fibrosis in Dupuytren’s disease (abstract), and teaches that TNFR2 was expressed in Dupuytren’s myofibroblasts, with TNFR2 expression being significantly higher than TNFR1 expression (Fig. 3B). Verjee also teaches that TNFR2 appears to be crucial for promoting profibrotic responses, and states that these observations were consistent with the Theiss data in which myofibroblasts from wild-type and TNFR1-deficient mice showed increased collagen accumulation in response to TNF treatment, whereas myofibroblasts from TNFR2-deficient mice did not show increased collagen accumulation (see above). Thus, Verjee supports a broader application of Theiss than the intestinal myofibroblasts they tested.
Faustman teaches TNFR2 antagonists for treatment of various disorders, including anti-TNFR2 antagonist antibodies (see claims 51-62; p. 20, lines 23-39).
Faustman further teaches anti-TNFR2 antibodies which bind two different epitopes of TNFR (i.e. bispecific) and inhibit activation of TNFR2 (see p. 20, lines 28-29, see also claim 58). Faustman teaches that its anti-TNFR2 antibodies can be humanized or antigen-binding fragments thereof, as required by claim 39 (claim 58). Faustman teaches anti-TNFR2 antagonist antibodies of the IgG class (Table 1, p. 30), and teaches that its antibodies can be bispecific (claim 58). Similarly, Faustman teaches that its antibodies can be antigen-binding fragments such as Fab and ScFv fragments (claim 58), and one of ordinary skill could have easily envisioned antibodies which comprise Fab or ScFv fragments and which exhibit bispecificity, such as for two different epitopes of TNFR2, as required by claim 40 (p. 20, lines 28-29).
Regarding claim 41-42, Faustman teaches that its antibodies can be administered via intravenous, subcutaneous, oral, intramuscular, intracranial, or intraarterial administration (p. 28, lines 3-9).
Regarding claims 43-45, Faustman teaches the administration of the therapeutics daily, weekly, or monthly (page 28 in lines 3-9).
Regarding claim 46, Faustman teaches that its antibodies can be administered in an amount from 1 mg to 400 mg per dose, depending on the patient’s state of health (p. 27, lines 31-33).
It would have been obvious at the time the application was filed to substitute the TNFα antagonist of the method of treatment of Nanchachal with the anti-TNFR2 bispecific antibody of Faustmann. One of skill in the art would have been motivated by the teaching of Theiss and Verjee teaching TNFR2 as a preferred target in the treatment of fibrotic conditions in general and Dupuytren’s disease specifically. Nanchahai teaches that Dupuytren’s disease can be treated by inhibition of TNFα and that disease progression of Dupuytren’s disease is from TNF binding to its receptors. Nanchahai also teaches that collagen accumulation is a pathological feature of Dupuytren’s disease, with inhibition of collagen accumulation being therapeutically beneficial. Theiss shows that TNFR2 is responsible for collagen accumulation in myofibroblasts and Verjee shows that myofibroblasts from Dupuytren’s patients exhibit high levels of TNFR2, Faustmann provides TNFR2 specific antagonists for use in the treatment of disease either as a monospecific or in bispecific binding molecules. One of ordinary skill in the art would have been motivated to improve the method of Nanchachal which recites a generic TNFα antagonist with a TNFα antagonist with more specific targeting and to use the method of treatment in other fibrotic conditions as Nanchachal teaches a broader applicability of the method of the claims than its sole use in Dupuytren’s disease. Theiss and Verjee provide a rationale for targeting TNFR2 as the actual cause of disease state and not inhibiting TNFR1 would be expected to decrease side effects from the method of Nanchachal. There would have been a reasonable expectation of success as it is a substitution of a generic TNFα antagonist for a specific species of TNFα antagonist and Theiss and Verjee teach towards inhibition of TNFR2 only for the method of treating fibrotic conditions generally and Dupuytren’s disease specifically.
Applicant Arguments
Applicant argues that TNFR2 antagonist is not a species of TNFα antagonist based on the writing of Nanchahal (Of Record) applicant cites page 17 in lines 4-12 of Nanchahal in support of this stating Nanchahal does not describe a TNFR2 antagonist as a species of TNFα antagonist.
Applicant argues that TNFα and TNFR-2 are distinct biological entities as TNFα is an inflammatory cytokine and TNFR2 a receptor.
Applicant argues that effectiveness of a method of treatment by administering a TNFα antagonist cannot reasonably be assumed to extend to TNFR2 antagonist as TNFα antagonists target TNFα the ligand and TNFR2 antagonists target the receptor.
Applicant argues that Faustman does not teach an early or established disease state of Dupuytren’s disease.
Applicant argues there would be no expectation of success as the art does not teach a TNFR2 antagonist in the patient population of early or established disease state of Dupuytren’s disease.
Applicant argues the art of Theiss and Verjee only establishes the presence of TNFR2 in the patient population of early or established disease state of Dupuytren’s disease.
Response to Arguments
Applicant's arguments filed 04/02/2026 have been fully considered but they are not persuasive.
The art rejection does not rely upon the type of protein being bound by the antagonist. TNFα is a cytokine that binds TNFR1 and TNFR2 as part of the TNF pathway. Nanchachal teaches a proposed mechanism for pathogenesis in Dupuytren’s disease that acts via TNFα binding TNFR teaching binding to receptors as playing a role in Dupuytren’s disease (Figure 19). TNFα acts through binding TNFR1 and 2 and inhibiting the ligand or the receptor will lead to inhibition of TNF α as shown in Figure 8 of Theiss and Figure 19 of Nanchahal both shown below.
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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).
Nanchachal is relied upon to teach the targeting of the TNF pathway by inhibition in the treatment of the patient population of the claims. Nanchachal further teaches towards the role of TNFR1 and TNFR2 in the patient population of early or established disease state of Dupuytren’s disease.
Theiss and Verjee are relied upon to establish that TNFR2 is present to be targeted in the patient population of interest.
Faustmann is relied upon to teach TNF pathway inhibition by TNFR2 inhibition using known in the art etanercept.
Rejections Maintained
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 38-46 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9,138,458 (Of Record) in view of Nanchachal (WO 2012/056044 A1) (Of Record), Theiss et al (J. Biol. Chem., 2005, 280(43):36099-36109) (IDS), Verjee et al (Proc. Natl. Acad. Sci. USA, 2013, 110(10):E928-E937) (IDS), and Faustman (WO2014/124134) (Of Record).
The patent recites a method of treating the fibrotic condition Dupuytren’s disease by administering an TNFα antagonist. The patent recites the direct administration to the location of fibrosis. The patent recites the method comprises the administration of an antagonist that is an antibody Claims 1-9),
The patent does not recite the method comprising the administration of an antagonist that acts on TNFR2 and not TNFR1.
The teachings of Nanchachal, Theiss, Verjee, nd Faustman from the previous art rejections are incorporated here in full.
It would have been obvious at the time the application was filed to substitute the TNFα antagonist of the method of treatment of Nanchachal with the anti-TNFR2 bispecific antibody of Faustmann in view of Theiss and Verjee.
It would have been obvious at the time the application was filed to substitute the TNFα antagonist of the method of treatment for Dupuytren’s disease recited by the patent with the anti-TNFR2 bispecific antibody of Faustmann in view of in view of Theiss and Verjee. Theiss and Verjee teachTNFR2 as a preferred target in the treatment of Dupuytren’s disease specifically and fibrotic conditions in general, as Nanchahal teaches treatments for Dupuytren’s disease for use in varying fibrotic conditions. Nanchahal teaches that fibrotic conditions including frozen shoulder, periarticular fibrosis, and Dupuytren’s disease can be treated by inhibition of TNFα. Nanchahal also teaches that collagen accumulation is a pathological feature of Dupuytren’s disease, with inhibition of collagen accumulation being therapeutically beneficial. Theiss shows that TNFR2 is responsible for collagen accumulation in myofibroblasts and Verjee shows that myofibroblasts from Dupuytren’s patients exhibit high levels of TNFR2, Faustmann provides TNFR2 specific antagonists for use in the treatment of disease either as a monospecific or in bispecific binding molecules. One of ordinary skill in the art would have been motivated to improve the method of the patent which recites a generic TNFα antagonist with a TNFα antagonist with more specific targeting. Theiss and Verjee provide a rationale for targeting TNFR2 as the actual cause of disease state and not inhibiting TNFR1 would be expected to decrease side effects from the methods of the patent and Nanchachal. There would have been a reasonable expectation of success as it is a substitution of a generic TNFα antagonist for a specific species of TNFα antagonist and Theiss and Verjee teach towards inhibition of TNFR2 only for the method of treating fibrotic conditions generally and Dupuytren’s disease specifically.
Conclusion
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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