DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on 4/8/26 has been entered. No amendments are indicated. Claims 1-3, 5-7, 11-15 and 20-23 are pending.
Election/Restrictions
Applicants' election without traverse of Group I, claim 7, in so far as drawn in the alternative to a method for treating a disorder characterized with aberrant cartilage formation and/or osteoclast resorption in a subject having a HLA-B27 mutation by administering a TGF-β inhibitor, in the reply filed on 4/8/26 is acknowledged. As set forth in the restriction requirement, claims 1-3 and 5-6 are linking claims that link Groups I-III and thus will be examined together with elected invention Group I.
Claims 11-15 and 20-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group IV), there being no allowable generic or linking claim.
The elections of (1) ankylosing spondylitis as the species of disorder, and (2) the “(1D11)” antibody as the species of TGF-β inhibitor, are also acknowledged.
Claims 1-3 and 5-7 are under consideration.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because (1) in part it is directed to compositions but the pending claims are all directed to method; and (2) in part it is directed to methods of treating disorders characterized with TGF-beta activity, but the claims of the elected group are directed to treating a disorder characterized by aberrant cartilage formation and/or osteoclast resorption; and (3) the claimed method encompasses any means of treatment but the elected invention is directed to a TGF- β inhibitor. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “Methods for Treating Disorders Characterized by Aberrant Cartilage Formation or Osteoclast Resorption with a TGF- β Inhibitor”.
---The disclosure is objected to because it contains seven embedded hyperlinks (browser-executable code) at page 54, line 19 and page 55, lines 3, 9, 14, 16, 21 and 24. Applicant is required to delete the embedded hyperlinks; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01 (VII).
---At pages 7 (line 9) and 23 (line 21), “Paget disease” should be “Paget’s disease”.
---At page 22, line 30, the sentence is missing a concluding period.
Appropriate correction is required.
Claim Objections
Claims 1-3 and 5-7 are objected to because of the following informalities:
In claim 1, line 8, the abbreviation “HLA-B” should be accompanied by the full terminology the first time it is used in a series of claims, i.e., “HLA-B (human leukocyte antigen B) gene”.
In claim 1, line 8, the abbreviation “TGF-β” should be accompanied by the full terminology the first time it is used in a series of claims, i.e., “TGF-β (transforming growth factor β)”.
In claim 1, there should be an “and” at the end of line 7 between the two “wherein” clauses.
In each of claims 2, “Paget disease” should be “Paget’s disease”.
In claim 6, line 1, “is small molecule” should be “is a small molecule”.
In claim 6, line 2, “a nucleic acid” should be “or a nucleic acid”.
In claim 6, line 3, the “and” should be an “or”.
Claim 6, line 3, contains an extraneous parenthesis before the final period.
Claim 7 is objected to for encompassing the subject matter of non-elected inventions Group II and Group in the alternative. The subject matter expressly directed to non-elected inventions should be recited in separate claims.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Improper Markush Grouping Rejection
Claim 7 is rejected on the basis that each contains or encompasses an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the group (i.e., alternatives from which a selection is to be made in the context of a combination or process) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
In claim 7, the Markush grouping in lines 1-2 that “the agent is a TGF-β inhibitor or a retinoic acid agonist or an angiotensin II receptor antagonist” is improper for the following reasons. First, because TGF-β, retinoic acid and an angiotensin II receptor (ATII receptor) are distinct biomolecules, with different cellular functions, the art does not recognize inhibitors/antagonists of each as belonging to the same class. Second, while each of the inhibitors/antagonists share a common use in the claimed method, they do not share a structural similarity. Each type of inhibitor encompasses a genus of molecules that are structurally discrete from those of the other genus. For example, each alternative encompasses an inhibitor that is an antibody, but because each binds to a different target (e.g., TGF-β, retinoic acid or ATII receptor), each antibody has a different set of complementarity determining regions (CDRs) and thus does not share the same structure.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 6 and 7 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 pre-AIA the applicant regards as the invention.
In claim 6, use of the terms “e.g.” (line 2) and “etc.” (line 3) render the claim indefinite. The phrase “e.g.” (which means “for example”) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The term “etc.” is indefinite because it is unclear what is encompassed by the alternative.
In claim 7, use of the term “such as” in lines 3, 5, 10 (two instances) and 11 (two instances). The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In claim 7, line 4, Galunisertib is listed as a type of antibody inhibitor of TGF-β, but Galunisertib is a small molecule.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 112(a), written description
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 1-3, 5 and 6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The instant claims are directed to a process with the intended goal of treating, delaying progression of, or reducing the severity of a disorder in a subject having an HLA-B27 mutation (in the HLA-B gene), and wherein the disorder is characterized with aberrant cartilage formation and/or osteoclast resorption. The method achieves this goal by a single method step of administering “a therapeutic agent capable of hindering and/or inhibiting aberrant cartilage formation and/or osteoclast resorption within the joints, muscles, tendons, ligaments, connective tissue, and/or bones experiencing or at risk of experiencing ankylosis”. The elected invention under consideration is directed to such a method wherein the agent is an inhibitor of transforming growth factor β (TGF-β), with the elected species being a specific anti-TGF-β antibody known as 1D11. The elected species of disease under control is ankylosing spondylitis.
The specification provides working examples related to the characterization of TGF-β activity in ankylosing spondylitis; specifically, Examples I-V. These examples report results demonstrating “that TGF-β activity was significantly increased at early inflammatory stage of AS” (¶ 103, published application) and “osteoclast remodeling of bony fused spine activates TGF-β in coupling new bone formation and angiogenesis to promote progression of AS” (¶ 109). In view of these results, the specification suggests that inhibition of TGF-β activity as therapy for AS.
The “TGF-β inhibitor” of the elected invention encompasses a genus compounds having a variety of structures, including the various antibodies, small molecules, antisense oligonucleotides and vaccines, aptamers, and soluble receptor proteins expressly recited in dependent claim 7. The teachings of the prior art support knowledge of a genus of TGF-β inhibitors; e.g., as reviewed by Ciardello et al, Oct 2020. Annals of Oncology. 31(10): 1336-1349 (available on-line Jul 2020); and Lee et al, Dec 2020. J Cancer Prev 25(4): 213-222. Per MPEP 2163, with respect to written description, “What is conventional or well known to one of ordinary skill in the art need not be disclosed in detail”. As such, it is considered that claimed method possesses written description with respect to the genus of TGF-β inhibitor to be administered.
However, the broadest claims are directed to any therapeutic agent capable of hindering and/or inhibiting aberrant cartilage formation and/or osteoclast resorption within joints, muscles, tendons, ligaments, connective tissue, and/or bones experiencing or at risk of experiencing ankylosis. These claims are genus claims because they encompass use of a genus of agents with the required functionality. No particular structure is required, and a vast range of potential structures are encompassed; i.e., dependent claim 6 indicates that the agent can be a small molecule, polypeptide, peptide, antibody or nucleic acid. However, a product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function; i.e., the structure of one therapeutic agent (i.e., a TGF-β inhibitor) does not provide predictability regarding other agent structures having the same functionality.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
Per MPEP 2163, "A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
In support of the genus of therapeutic agents having the required activity (hindering and/or inhibiting aberrant cartilage formation and/or osteoclast resorption within joints, muscles, tendons, ligaments, connective tissue, and/or bones experiencing or at risk of experiencing ankylosis), the specification provides three categories of agents: the aforementioned subgenus of TGF-β inhibitors, 12 species of retinoic acid agonists, and 2 species of angiotensin (AT) II receptor antagonists. These limited examples fail to correspond to the scope of the genus of therapeutic agents, which can having any type of molecular structure. The specification envisions a structurally diverse genus of agents, defined solely by activity, but fails to describe with specificity a representative number of examples corresponding in scope to this genus. The specification fails to describe what changes can be made to the disclosed species to produce species having different structures and still retain the required functionality. As such, the specification fails to disclose relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only a method of claim 1 wherein the therapeutic agent is a TGF-β inhibitor, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 1-3 and 5-7 are rejected under 35 U.S.C. 103(a) as being unpatentable over Levi et al, WO 2019/157342 A1, published 8/15/19, and further in view of Guo et al, Aug 2019, Journal of Orthopaedic Surgery and Research. 14:253; 6 pages as printed. The earliest date to which the instant application claims priority is 10/28/20.
Claim 1 encompasses the elected invention (Group I), which is directed to a method for treating a disorder characterized with aberrant cartilage formation and/or osteoclast resorption in a subject having a HLA-B27 mutation, comprising administering a therapeutic agent that is a TGF-β inhibitor. The disorder encompasses both ankylosing spondylitis and heterotopic ossification as recited in dependent claims 2 and 3.
Levi teaches the use of a “TGFβ antagonist (inhibitor)” to “treat heterotopic ossification (HO)” (page 1, lines 26-27; see also claim 1). Thus, the teachings of Levi meet all of the limitations of claim 1 with respect to treatment of heterotopic ossification, except that Levi does not teach that the subject has a HLA-B27 mutation.
Guo teaches that ankylosing spondylitis (AS) “is a kind of unexplained chronic inflammatory disease that predominantly affects axial joints” (page 1). Guo teaches that nearly 90% of human patients with AS having the HLA-B27 allele (page 1). Guo teaches that the literature reports that “in AS patients after THA [total hip arthroplasty], the incidence rate of heterotopic ossification was 11-76%” (page 4).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the method of treatment of heterotopic ossification (HO) with a TGF-β inhibitor taught by Levi and apply it to a patient having AS and the HLA-B27 allele, and further experiencing HO after THA as taught by Guo. The person of ordinary skill in the art would have been motivated to make such a change in order to treat HO in a specific patient population that occurrence of the condition is taught to be correlated with; i.e., patients with AS (90% of which have the HLA-B27 allele) and having had THA. The person of ordinary skill in the art would have had a reasonable expectation of success in treating HO in such a patient population because Levi teaches use of TGF-β inhibitor for treatment of HO in general, and in the absence of any contrary indications, the skilled artisan would reasonably expect that the treatment would work to treat HO in that subset of patients having AS, a HLA-B27 allele and THA. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Claims 2 and 3 encompass a method of claim 1 wherein the disorder is ankylosing spondylitis (AS) or heterotopic ossification (HO) (claim 2) or wherein the subject is a human experiencing AS or HO. The method obvious over the teachings of Levi in view of Guo that meets the limitations of claim 1 is directed to the method wherein the subject is a human patient having both AS and HO. As such, the method obvious over the teachings of Levi in view of Guo that meet the limitations of claim 1 also meet the limitations of claims 2 and 3.
Claim 5 encompasses a method of claim 1 wherein the agent is capable of inhibiting TGF-β activity within bones experiencing ankylosis. The method obvious over the teachings of Levi in view of Guo that meets the limitations of claim 1 is directed to an agent capable of inhibiting TGF-β activity within a patient having AS, which is characterized by bones experiencing ankylosis. As such, the method obvious over the teachings of Levi in view of Guo that meet the limitations of claim 1 also meet the limitations of claim 5.
Claims 6 and 7 encompass the method of claim 6 wherein the agent, i.e., TGF-β inhibitor, is an antibody. Levi further teaches that the TGF-β antagonist is an antibody; e.g., at page 3, lines 13-16. As such, it would have further been obvious to use an antibody inhibitor of TGF-β when practicing the method obvious over the teachings of Levi in view of Guo that employs an inhibitor of TGF-β.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated-interview-request-air-form.
/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
Prosecution Insights