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 amendment of 11/7/25 has been entered in full. Claims 13 and 14 are canceled. Claims 2-12 and 15-19 are amended. New claims 20 and 21 are added. Claims 1-12 and 15-21 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicants' election without traverse of Group I, claims 1-12 and 15-19, in the reply filed on 11/7/25 is acknowledged. All of the claims of non-elected Group II have been canceled. New claims 20 and 21 are directed to a method comprising a single active step of administering only a TLR7/8 inhibitor; i.e., not in combination with a TNFα inhibitor. This method is deemed a separate inventive group, Group III, and does not share the same or corresponding technical feature with the main invention (Group I) because while Group I is drawn to a use of a combination (TLR7/8 inhibitor and TNFα inhibitor), Group III is drawn only to use of one of the subcombinations (TLR7/8 inhibitor). The claims of Group III are evidence that the subcombination can be used separately from the combination. See MPEP § 821.04(a) for restriction between combination and subcombination inventions. Furthermore, the claims of Group I are rejected over the prior art (see below), and therefore any technical feature linking the inventions of Groups I and III does not constitute a special technical feature as defined by PCT rule 13.2, as it does not define a contribution over the prior art.
Claims 20 and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The elections of (1) the compound of Formula (I) as the species of TLR7/8 inhibitor, and (2) etanercept as the species of TNFα inhibitor, in the reply are also acknowledged. Claim(s) 4-7 and 16-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
1-3, 8-12 and 15 are under consideration, as they read upon the elected species.
Specification
The disclosure is objected to because of the following informalities:
The title of the invention is not descriptive because it is directed generally to any treatment of rheumatoid arthritis (RA), but the claimed invention is limited to treating RA with a combination of a TLR7/8 and TNFα inhibitors. A new title is required that is clearly indicative of the invention to which the claims are directed. The following is suggested: “METHODS OF TREATING RHEUMATOID ARTHRITIS WITH A COMBINATION OF TLR7/8 AND TNF ALPHA INHIBITORS”
Appropriate correction is required.
Claim Objections
Claims 1-3, 8-12 and 15 are objected to because of the following informalities:
In claim 1, the acronyms “TLR7/8” and “TNFα” should be accompanied by the full terminology the first time each appears in a series of claims; e.g., “a TLR7/8 (toll-like receptors 7 and 8) inhibitor” and “a TNFα (tumor necrosis factor α) inhibitor”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
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 § 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, 8-12 and 15 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 method intended for the treatment of rheumatoid arthritis. The method is intended to achieve this goal via a single step of administration, to a subject, of a therapeutically effective dose of a TLR7/8 antagonist in combination with a therapeutically effective dose of a TNFα inhibitor. While the claims are directed to a method of use of a combination of products rather than a per se combination of products, practicing said method of use requires a written description of each of the products to be used in the method; i.e., in this case, the requisite inhibitors.
With respect to the first element of the administered combination, which is a “TLR7/8 inhibitor”, this e is only defined functionally in the specification as something that “inhibits the function of TLR7, TLR8, or both TLR7 and TLR8”. TLR7 and TLR8 are art-recognized terms for the proteins “Toll-Like Receptor 7” and “Toll-Like Receptor 8”. The specification further provides examples of structures that may have such an inhibitory function, including “antibodies, small molecules, and millimolecular compounds” (page 4, lines 25-27), but does not require any particular structure for said inhibitor. The elected species of TLR7/8 inhibitor under consideration is a small molecule compound with the structure shown in dependent claim 2, which the specification further labels “Formula (I)” (page 5, starting at line 28). The specification further teaches that the full name of the compound is “2-(4-(2-(7,8-dimethyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide”, and that the prior art reference of WO 2018/005586 (cited on the cited on the 5/7/24 IDS) teaches its “discovery and synthesis” (page 6, lines 1-4).
With respect to the other element of the administered combination, a “TNFα inhibitor”, this term is also only defined structurally by the instant specification, which defines it as “a drug that blocks the activity of tumor necrosis factor α (TNFα)” (page 5, lines 6-7). Again, no particular structure is required, but the inhibitors may include “antibodies, small molecules and millimolecular compounds” (page 5, lines 6-7). The elected species under consideration is etanercept, commercially known as Enbrel, to which the inhibitor is limited in dependent claims 3 and 15.
Thus the claims are genus claims, because they are directed to a method of use of a genus of compounds having any structure capable of inhibiting TLR7 or TRL8, and also a genus of compounds having any structure capable of inhibiting TNFα. As noted above, the specification envisions that each genus includes at least antibodies, small molecules and millimolecular compounds, the latter of which is a term not further explained. However in view of the lack of any recitation of structure in the broadest claims, the claims also encompass other structures having the required inhibitory activity, such as proteins, peptides, nucleic acids, lipids, cardohydrates, inorganic compounds, and more. Each category of structure, such as antibodies, is a distinct subgenus that encompasses many multiple species having the required functionality.
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; e.g., the structure of one TLR7/8 inhibitor, such as the elected species under consideration, does not provide predictability regarding the range of other compound structures having the same functionality. Furthermore, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g. TLR7/8) is not in and of itself sufficient to provide a description of the genus of inhibitors of said target.
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).
In support of the claimed genus of “TLR7/8 inhibitors”, the specification provides a single example, which is the elected species under consideration. No other small molecule inhibitors of TLR7 or TLR8 are described, and no inhibitors having other structures are described. A description of a single small molecule inhibitor that is defined by its molecular structure is not representative of a subgenus of small molecule inhibitors having other structures, let alone the broader genus of inhibitors include antibodies, protein, peptides, nucleic acids and more. 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 claimed genus of “TNFα inhibitor”, the specification provides examples of five species of structures having the ability to inhibit TNFα. These include etanercept, which is a fusion of the extracellular TNF-binding domain of the TNFR2 receptor with an Fc region, and four anti-TNFα monoclonal antibodies, including infliximab, certolizumab, golimumab and adalimumab. A description of a single fusion protein that is defined by its molecular structure is not representative of a subgenus of protein-based inhibitors, let alone the broader genus of inhibitors include antibodies, protein, peptides, nucleic acids and more. Even the description of four monoclonal antibodies are not representative of the subgenus of antibody-based inhibitors, as the genus of antibodies binding to TNFα includes hundreds of members.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). The mature TNFα protein is 157 amino acids in length. Thus, even considering only continuous epitopes, TNFα comprises a multitude of different regions of five amino acids that can serve as epitopes; i.e., residues 1-5, 2-6, 3-7, up to residues 153-157. While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure of other antibodies that bind to the same epitope or to the other epitopes in the same protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36). Thus, there are at least hundreds of different antibody structures that bind to the TNFα protein, and a large subset of these will also function as antagonists to the protein (by binding the TNFα and blocking its function), and the instant specification only provides examples of 4 such structures, which does not corresponding in scope to that which is claimed.
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 treating rheumatoid arthritis, comprising administering to a patient a therapeutically effective dose of a TLR7/8 inhibitor with the structure shown in Figure 2, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective dose of a TNFα inhibitor that is etanercept, 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).
Claim Rejections - 35 USC § 102
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 1-2 and 8-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/005586, published 1/4/2018 (cited on the 5/7/24 IDS). The earliest date to which the instant application claims priority is 6/22/20.
Claim 1 encompasses a method of treating rheumatoid arthritis comprising administering to a patient a therapeutically effective dose of a TLR7/8 inhibitor in combination with a therapeutically effective dose of a TNFα inhibitor. The TLR7/8 inhibitor of claim 1 encompasses the inhibitor of dependent claim 2, which is the elected species under consideration. The instant specification designates the inhibitor of claim 2 as Formula (I) and states that it is taught by the ‘586 publication (page 5).
‘586 teaches compounds that inhibit TLR7 and 8 (page 1), that include the same formula as shown in instant Formula (I); e.g., see page 73, line 10. ‘586 further teaches use of the compounds of the invention for treatment of autoimmune diseases such as rheumatoid arthritis (page 111, lines 6-7) and in a therapeutically effective amount (page 109, lines 18-23). ‘586 further teaches that for treatment of autoimmune diseases the compounds of the invention can be administered in combination with other suitable therapeutic agents (page 113, lines 11-13) and examples of such include TNFα inhibitors (page 113, lines 25-26). As such, the teachings of ‘586 anticipate claim 1.
Claim 2 limits the TLR7/8 inhibitor of claim 1 as indicated above; i.e., to the elected species and therefore is also anticipated by the teachings of ‘586.
Claim 8 encompasses a method of claim 1 wherein said dose of TLR7/8 inhibitor is in the range of 0.1 to 100 mg per day. ‘586 teaches that the dose can be “from about 0.5 to 100 mg” and can be given daily (page 115, lines 14-22). As such, the teachings of ‘586 also anticipate claim 8.
Claims 9-12 encompass a method of claim 1 wherein the two inhibitors are administered concurrently (claim 9), sequentially (claim 10), with the TRL7/8 inhibitor administered prior to the TNFα inhibitor (claim 11) or with the TNFα inhibitor administered prior to the TLR7/8 (claim 12). ‘586 further teaches that “other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds” (page 113, lines 30-32). As such, the teachings of ‘586 also anticipate each of claims 9-12.
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 3 and 15 are rejected under 35 U.S.C. 103(a) as being unpatentable over WO 2018/005586, published 1/4/2018 (cited on the 5/7/24 IDS), as applied to claim 1 above, and further in view of Ma et al, 2013. Biomedical Reports. 1: 177-184.
Claims 3 and 15 encompass the method of claim 1 (claim 3) or claim 2 (claim 15) wherein the TNFα inhibitor is etanercept.
The teachings of ‘586 that anticipate parent claims 1 and 2 are set forth above. ‘586 further teaches that the TNFα inhibitor can be a “soluble TNF receptor”, but does not teach that such an inhibitor is etanercept.
Ma reviews “TNF inhibitor therapy for rheumatoid arthritis” (see Title). Ma teaches that etanercept is one of several TNFα antagonists that “have been widely used for the treatment of RA” and further that etanercept is “effective and safe for patients with RA” (page 177). Ma further teaches that etanercept is “a genetically engineered protein comprising two molecules of the extracellular domain of TNF receptor II (p75) and the Fc portion of IgG1” (page 178).
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 rheumatoid arthritis comprising administering to a patient a therapeutically effective dose of a TLR7/8 inhibitor, including one with the structure recited in dependent claim 2, in combination with a therapeutically effective dose of a TNFα inhibitor taught by ‘586 and modify it to use etanercept as taught by Ma as the specific co-administered TNFα inhibitor. The person of ordinary skill in the art would have been motivated to make such a change because ‘586 teaches using a TNFα inhibitor in combination with the TLR7/8 inhibitor, and further specifies that such can be a soluble TNF receptor, but does not further teach the specific structure of the TNFα inhibitor, and Ma provides the missing information; i.e., by providing a specific example of a TNFα inhibitor comprising a soluble TNF receptor. The person of ordinary skill in the art would have had a reasonable expectation of success because Ma teaches etanercept is effective for the same purpose, i.e., treatment of rheumatoid arthritis. Thus, such a modified method represents a simple and predictable use of art-recognized species where an art-recognized genus is taught. Furthermore, per MPEP 2144.06, citing In re Kerkhoven, it is prima facie obvious to combine two treatments taught by the prior art for the same purpose, in order to form a third treatment to be used for the same purpose. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
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.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674