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 11/21/25 has been entered in full. Claims 1-7 and 13-14 are canceled. Claims 17, 19-20 and 23 are amended. New claims 26-36 are added. Claims 17 and 19-36 are pending.
Election/Restrictions
New claims 26-36 depend from claim 17 and are part of inventive Group II.
Applicants' election without traverse of Group II, currently all pending claims, in the reply filed on 11/21/25 is acknowledged.
The elections without traverse of (1) tafamidis as the species of TTR tetramer stabilizer, and (2) ATTR cardiomyopathy as the species of disease, in the reply are also acknowledged. Claim(s) 29-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 17, 19-28 and 36 are under consideration, as they read upon the elected species.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 20 is objected to because of the following informalities:
In claim 20, the conditions are inconsistently capitalized. This could be corrected by changing “Family Amyloid Polyneuropathy (FAP)” to “family amyloid polyneuropathy (FAP)”, “Senile Systemic Amyloidosis (SSA)” to “senile systemic amyloidosis (SSA)” and “Central Nervous System (CNS)” to “central nervous system (CNS)”.
Appropriate correction is required.
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 17, 19-28 and 36 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 diseases encompassed by the term “transthyretin amyloidosis (ATTR)”, effected via “inducing or promoting ATTR fibril clearance through antibody-dependent cellular phagocytosis (ADCP)”. The elected species of disease is ATTR cardiomyopathy. The method is intended to achieve this goal via a single step of administration, to a subject, of an anti-TTR antibody and either a TTR tetramer stabilizer or silencer. The elected species of the latter under consideration is tafamidis, which is a TTR tetramer stabilizer. 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 requires a written description of each of the products to be used in the method.
With respect to the first element of the administered combination, which is an anti-TTR antibody, this product is defined structurally as being an antibody, and functionally as being “anti-TTR”, with “anti” being art-recognized term indicating binding to the target antigen (here TTR). 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 TTR protein is 127 amino acids in length (see page 1286 of Ruberg et al, 2012. Circulation. 126: 1286-1300). Thus, even considering only continuous epitopes, TTR 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 123-127. 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 TTR protein.
With respect to the other element of the administered combination, a TTR tetramer stabilizer, this term is only defined functionally; i.e., stabilizing the TTR tetramer. No particular structure is required, but the specification indicates that the TTR stabilizers may be “small molecules”, which is a subgenus encompassing the elected species of tafamidis, a benzoazole derivative. However, in view of the lack of any recitation of structure in the broadest claims, the claims also encompass other structures having the required stabilizer activity, such as proteins, peptides, antibodies, nucleic acids, lipids, cardohydrates, inorganic compounds, and more.
Thus the claims are genus claims, because they are directed to a method of use of a genus of anti-TTR antibodies and a genus of TTR tetramer stabilizers.
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 anti-TTR antibody and the structure of one TTR tetramer stabilizer, 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. TTR) is not in and of itself sufficient to provide a description of the genus of antibodies binding TTR or the genus of compounds stabilizing TTR tetramers.
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 “anti-TTR antibody”, the specification provides examples of two monoclonal antibodies that bind TTR and have related sequences. Specifically, the specification teaches “the amino acid sequences of the variable heavy (VH) and light (VL) chain of human-derived monoclonal antibody NI-301.37F1 are disclosed in WO 2015/092077 A1 in FIG. 1 with SEQ ID NO: 10 and 53, respectively, corresponding to SEQ ID NO: 2 and 6 of the present sequence listing for the VH chain and SEQ ID NO: 12 corresponding to SEQ ID NO: 4 of the present sequence listing for the VL chain” (¶ 266, published application). However, a description of just two related monoclonal antibody sequences that are defined by molecular structure is not representative of the genus of anti-TTR antibodies to be used in the claim methods, which encompasses hundreds or more species. 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 TTR tetramer stabilizers, the specification provides three examples, tafamidis, diflunisal and AG10, each of which are small molecules with different molecular structures. No other small molecule stabilizers of TTR are described, and no description of how to the structure of the disclosed stabilizers describes other small molecule structures having the same functionality. No inhibitors having other structures are described; e.g., proteins or antibodies. A description of a three small molecule inhibitors that are defined by 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.
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 of treating transthyretin amyloidosis (ATTR) by inducing or promoting ATTR fibril clearance through ADCP comprising administering to a subject in need thereof an anti-transthyretin (TTR) antibody comprising a VH chain comprising the amino acid sequence of SEQ ID NO: 2 or 6 and a VL chain comprising the amino acid sequence of SEQ ID NO: 4 and a TTR tetramer stabilizer that is tafamidis, 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 § 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 17, 19-25, 27 and 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grimm et al, U.S. Patent Application 2016/0355576, published 12/8/16 (cited on the 1/16/25 IDS). The earliest date to which the instant application claims priority is 5/12/20.
Claim 17 encompasses a method of treating transthyretin amyloidosis (ATTR) by inducing or promoting ATTR fibril clearance through antibody-dependent phagocytosis (ADCP) comprising administering to a subject in need thereof an anti-transthyretin (TTR) antibody and a TTR tetramer stabilizer. The recitation of “treating … by inducing or promoting ATTR fibril clearance through ADCP” has been considered in the context of the entire claim, and is interpreted as an intended use for the method because it does not result in a manipulative difference between the method as defined by the steps and a prior art method teaching the same steps. See MPEP 2111.02. As such, for purposes of anticipation this intended use does not distinguish the claimed method from a prior art method comprising the same step(s). Thus, claim 17 encompasses a method comprising administering to a subject in need of treating ATTR an anti-TTR antibody and a TTR tetramer stabilizer.
The ‘576 publication teaches that “[t]he present invention generally relates to antibody-based therapy of transthyretin (TTR) amyloidosis”; specifically, antibodies that bind TTR (¶ 1). ‘576 further teaches that the antibodies can be administered with “other agents useful for treating a disease or disorder related to misfolded, misassembled, mutated, and/or aggregated TTR”, including “Agents which stabilize the TTR-tetramer” (¶ 321). As such, ‘576 teaches a method comprising administering a subject in need of treating ATTR an anti-TTR antibody and a TTR tetramer stabilizer. As such, the teachings of ‘576 anticipate claim 17.
Claim 19 encompasses the method of claim 17 wherein the antibody is administered sequentially with the stabilizer. ‘576 further teaches sequential administration of the other agents (¶ 321). As such, the teachings of ‘576 also anticipate claim 19.
Claim 20 encompasses the method of claim 17 wherein the ATTR is wild-type (wtATTR) or variant ATTR (vATTR) and the ATTR is associated with ATTR cardiomyopathy. The instant specification teaches that wtATTR is associated with the wild-type TTR protein, and that vATTR is associated with a mutated TTR protein (¶ 3). ‘576 further teaches that the invention includes treatment of “diseases associated with TTR amyloidosis” such as “Familial Amyloid Cardiomyopathy (FAC)” (¶ 2), and further that FAC is associated with a mutation in TTR (¶ 7), and thus this condition is “variant ATTR” as recited in claim 20. As such, the teachings of ‘576 also anticipate claim 20.
Claim 21 encompasses the method of claim 17 wherein the antibody is of the IgG1 class. ‘576 further teaches that antibodies of the invention can be IgG1 antibodies (¶ 123). As such, the teachings of ‘576 also anticipate claim 21.
Claim 22 encompasses the method of claim 17 wherein the antibody is a human-derived antibody. ‘576 further teaches that antibodies of the invention are “human-derived” antibodies (¶ 1). As such, the teachings of ‘576 also anticipate claim 22.
Claims 23 and 24 each encompass the method of claim 17 wherein the antibody comprises the VH and VL sequences of SEQ ID NO: 2 and 4. The instant application teaches that these are the VH and VL sequences of antibody NI-301.37F1 (¶ 266, published application). The exemplary anti-TTR antibodies of the invention of ‘576 include this same NI-301.37F1 antibody having the same VH and VL sequences; see Figure 1C of ‘576, which shows these same amino acid sequences. As such, the teachings of ‘576 also anticipate claims 23 and 24.
Claims 25 and 27 encompass the method of claim 17 wherein the stabilizer is tafamidis (claim 25) that is tafamidis meglumine (claim 27). ‘576 further teaches that the agents that stabilize the TTR-tetramer include Tafamidis Meglumin (¶ 321). As such, the teachings of ‘576 also anticipate claims 25 and 27.
Claim 36 encompasses the method of claim 36 wherein the subject is human. ‘576 further teaches that the subject of the invention includes a human patient (¶ 168). As such, the teachings of ‘576 also anticipate claim 36.
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 26 and 28 are rejected under 35 U.S.C. 103(a) as being unpatentable over Grimm et al, U.S. Patent Application 2016/0355576, published 12/8/16 (cited on the 1/16/25 IDS), as applied to claims 17, 19-25, 27 and 36 above, and further in view of the Label for VYNDAQEL/VYNDAMAX; issued 05/2019, distributed by Pfizer. 16 pages. Available at https://www.fda.gov/media/126283/download.
Claim 26 encompasses a method of claim 25 wherein the tafamidis is administered to the subject at a dose of 61 mg/day. Claim 28 encompasses a method of claim 27 wherein the tafamidis meglumine is administered to the subject at a dose of 80 mg/day.
The teachings of ‘576 that anticipate parent claims 25 and 27 are set forth above. While ‘576 teaches additional administration of an agent that stabilizes the TTR tetramer, including tafamidis meglumine, ‘576 does not specify a dosage for administration of such a drug.
The Label for VYNDAQEL/VYNDAMAX (hereafter “Label”) teaches that “VYNDAQEL and VYNDAMAX are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization” (page 2). The Label further teaches that “The recommended dosage is either VYNDAQEL 80 mg (four 20-mg tafamidis meglumine capsules) orally once daily or VYNDAMAX 61 mg (one 61-mg tafamidis capsule) orally once daily” (page 2).
With respect to claim 26, 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 comprising administering to a subject in need of treating ATTR an anti-TTR antibody and a TTR tetramer stabilizer as taught by ‘576, and modify the method to administer tafamidis at a dosage of 61 mg/day as taught by the Label. Because the Label teaches tafamidis meglumine and tafamidis as equivalents for treatment of cardiomyopathy associated with ATTR, it would have been obvious to use either one in place of the other for treatment of such a condition. Thus, use of tafamidis in place of tafamidis meglumine represents a simple substitution of one art-recognized equivalent for the other for use for the same purpose. Furthermore, the skilled artisan would have been motivated to administer tafamidis at 61 mg because ‘576 teaches administration of a TTR tetramer stabilizer, but does not further teach a specific dosage for such, and the Label provides the missing information; i.e., the Label teaches that 61 mg is the specific FDA-approved dosage for use of tafamidis for treatment of TTR amyloidosis. The person of ordinary skill in the art would have had a reasonable expectation of success because the Label teaches use of the tafamidis for treatment of the same condition as ‘576; i.e., cardiomyopathy associated with ATTR. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
With respect to claim 28, 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 comprising administering to a subject in need of treating ATTR an anti-TTR antibody and a TTR tetramer stabilizer, for example tafamidis meglumine, as taught by ‘576, and modify the method to administer the tafamidis meglumine at a dosage of 80 mg/day as taught by the Label. The person of ordinary skill in the art would have been motivated to make such a change because ‘576 teaches administration of tafamidis meglumine, but does not further teach a specific dosage for such, and the Label provides the missing information; i.e., the Label teaches that 80 mg is the specific FDA-approved dosage for use of tafamidis meglumine for treatment of TTR amyloidosis. The person of ordinary skill in the art would have had a reasonable expectation of success because the Label teaches use of the tafamidis meglumine for treatment of the same condition as ‘576; i.e., cardiomyopathy associated with ATTR. 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