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 .
Claims 1-8, 11, 13, 16-18, 20-24 and 26-27 are pending.
Election/Restrictions
Applicants' election with traverse of Group I, claims 1-8, 11, 13, 16, 20-24, 26 and 27, in the reply filed on 9/10/25 is acknowledged.
The traversal is on the ground(s) that the polynucleotides of Group II “share a corresponding technical” feature with the proteins of Group I; Applicants point to guidance from WIPO regarding PCT Rule 13.1. This argument has been fully considered and is found persuasive, and the restriction between the two groups is hereby withdrawn.
The elections without traverse of (1) TNFα as the species of target, and (2) 177Lu as the species of cytotoxic agent, in the reply filed on 9/10/25 are also acknowledged. Each elected species reads on each pending claim.
Claims 1-8, 11, 13, 16-18, 20-24 and 26-27 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.
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the following reasons. A Sequence Listing was most recently filed on 4/27/23.
---The amino acid sequences disclosed in Figure 1D (1 sequence) and Figure 7 (20 sequences) are not included in the current Sequence Listing. The Sequence Listing must be updated to include each sequence, and then each sequence should be identified by the appropriate sequence identifier (SEQ ID NO) in either the figure or the Brief Description of the figure in the specification.
---Page 16 of the specification shows four nucleic acid sequences that are not accompanied by the required sequence identifier. These appear to correspond to SEQ ID NO: 2-5 in the Sequence Listing; if so, the appropriate sequence identifier should be added to the specification where each sequence appears.
---Table 4 on page 25 shows 12 amino acid sequences that are not included in the Sequence Listing. It is noted that the “..” symbols shown in each sequence correspond to defined residues (i.e., indicating non-mutated positions), and thus each sequence is Table 4 represents a sequence of 21 defined amino acids. As such, the Sequence Listing must be updated to include each sequence, and then each sequence should be identified by the appropriate sequence identifier (SEQ ID NO).
---SEQ ID NO: 1 as shown in claim 1 and the specification at ¶ 10 and 46 does not include the “preferably not Cys, Gly or Pro” clause for each of positions 11, 15, 19, 27, 33, 35, 36, 38, 39 and 43-46. See also the rejection of the claims under 35 U.S.C. 112(b) set forth below.
Applicants must comply with the requirements of the sequence rules (37 CFR 1.821 - 1.825).
Specification
The disclosure is objected to because of the following informalities. Paragraphs refer to the substitute specification filed on 4/27/23.
---The title of the invention is not descriptive because it is directed generally to any bispecific protein, but the claims are limited to a bispecific protein that is an engineered antigen binding domain of Protein G that binds to HAS and another target. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “BISPECIFIC PROTEIN COMPRISING AN ENGINEERED ANTIGEN-BINDING DOMAIN OF PROTEIN G CAPABLE OF BINDING ALBUMIN AND ANOTHER TARGET”
---The sentence in ¶ 19 does not end with a period.
---The specification is objected to for not complying with the requirements for sequences noted above.
Appropriate correction is required.
Claim Objections
Claims 8, 11 and 13 are objected to because of the following informalities:
In claim 8, lines 2-3, each instance of “neither” should be “none”.
In claim 11, line 1, “protein claim 1” should be “protein of claim 1”.
In claim 11, lines 2-3, each instance of “neither” should be “none”.
In claim 13, lines 2-3, each instance of “neither” should be “none”.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
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 1-8, 11, 13, 16-18, 20-24 and 26-27 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.
Independent claim 1 requires the claimed bispecific protein to encompass the sequence of SEQ ID NO: 1, but the sequence of SEQ ID NO: 1 shown in the claim does not exactly match the sequence of SEQ ID NO: 1 included in the sequence listing (filed on 4/8/23). Specifically, SEQ ID NO: 1 in the Sequence Listing includes the descriptor “preferably not Cys, Gly or Pro” at each of positions 11, 15, 19, 27, 33, 35, 36, 38, 39 and 43-46. Thus, claim 1 is indefinite because it is unclear whether these descriptors applies to SEQ ID NO: 1 as recited in claim 1 or not. Furthermore, if these descriptors do apply to the SEQ ID NO: 1, they are further indefinite because they recite exemplary language, analogous to “such as”, and it is unclear whether the limitations following each term are part of the claimed invention. See MPEP § 2173.05(d). In this regard, the claim could be rendered definite by correcting SEQ ID NO: 1 in the Sequence Listing to match the SEQ ID NO: 1 shown in claim 1 and the specification (i.e., at ¶ 10, 46), neither of which include the “preferably” clauses when describing these positions.
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(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.-Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Per MPEP 608.01(n).III, “If the dependent claim does not comply with the requirements of 35 U.S.C. 112(d), the examiner should reject the dependent claim under 35 U.S.C. 112(d) rather than objecting to the claim” and “a dependent claim must be rejected under 35 U.S.C. 112(d) if it omits an element from the claim upon which it depends or it fails to add a limitation to the claim upon which it depends”.
Dependent claim 16 limits the bispecific protein of claim 1 to one wherein positions 1, 4, 5, 8, 12, 16, 25, 31, 34 and 42, each and independently, are conserved, or are conservatively substituted. The term “conserved” is interpreted as being “unchanged”, and “conservatively substituted” is interpreted as being a conservative substitution as described at ¶ 64 of the specification.
However, parent claim 1 is limited to a bispecific protein that comprises SEQ ID NO: 1 with the proviso that at least one of positions 22, 23, 26 and at least one of positions 2, 3, 6, 7, 10, 13 and 14 have been mutated in relation to SEQ ID NO: 1 to obtain the affinity to the other target. As such, claim 1 is limited to a bispecific protein comprising the sequence of SEQ ID NO: 1 at positions 1, 4, 5, 8, 12, 16, 25, 31, 34 and 42. As such, claim 1 does not encompass a conservative substitution at any of positions 1, 4, 5, 8, 12, 16, 25, 31, 34 or 42. As such, claim 16 encompasses embodiments outside the scope of parent claim 1.
Therefore, dependent claim 16 is of improper dependent form because it fails to further limit the subject matter of parent claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-8, 11, 13, 16-18, 20-24 and 26-27 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 claimed invention is a product; specifically, a bispecific protein capable of binding the blood plasma protein Human Serum Albumin (HSA) and another target, and which comprises the sequence of SEQ ID NO: 1, a sequence of 46 amino acids, that is defined at 32 residues (4 of which may be 2 or 3 different amino acids) and undefined (any amino acid) at 14 residues, with the further proviso that at least one of positions 22, 23, and 26 and at least one of positions 2, 3, 6, 7, 9, 10, 13 and 14 have been mutated in relation to SEQ ID NO: 1. Thus, the amino acid sequence of SEQ ID NO: 1 is a reference sequence, and the claimed invention is directed to mutated variants of this reference. The elected species of other target is the cytokine tumor necrosis factor α (TNFα).
The specification teaches that the sequence of SEQ ID NO: 1 is derived from the albumin-binding domain (ABD) of Streptococcal Protein G (¶ 42). This source can be mutated to make proteins that bind to other targets, and these proteins are termed ADAPT (ABD Derived Affinity Protein) (¶ 7). These function as an “alternative scaffold”, a small-sized alternative to an antibody (¶ 4). Furthermore, binding to HAS imparts a longer-half-life to the small protein (¶ 42). In the claimed invention, “the proposed binding surface of the desired target has been moved from helix 1 and helix 3 to helix 1 and helix 2 of the ADAPT molecule” (¶ 9), to overcome a problem with lack of simultaneous binding to HAS and the target protein (¶ 8).
In view of the limitations of claim 1, the bispecific protein encompasses a vast genus of variant protein structures. First, the proteins include those with any mutation at positions 2, 3, 6, 7, 9, 10, 13, 14, 22, 23 and 26, meaning that each of these 11 positions can be any of the 19 natural amino acids; i.e., any natural amino acid other than what is shown in SEQ ID NO: 1 at that position. Furthermore, SEQ ID NO: 1 itself allows for any of the 20 natural amino acids at 14 positions (11, 15, 17, 19, 27, 33, 35, 36, 38 and 39 and 43-46). Together, these 25 positions make up more than half of the reference protein of SEQ ID NO: 1, which consists of 46 amino acids. Furthermore, SEQ ID NO: 1 has 4 more positions (20, 23, 26 or 40) that can be 2 or 3 different amino acids. Even if just considering the 11 positions that can be mutated, the genus of potential structures encompasses 1911 variants, or 1.16 x 1014 variants. The 14 positions of SEQ ID NO: 1 that allows for any amino acid encompass 2014 variants, or 1.6 x 1018 variants. Together, these encompass 1.9 x 1032 variant proteins.
The claims further require that the bispecific protein has two functions: binding to HSA and to another target protein, e.g., TNFα. The claims also recite six other target proteins, but the claim 1 encompasses any possible target structure, which broadly includes not just proteins but any other type of organic or inorganic molecule. Thus, the claimed product is defined structurally by its amino acid sequence, and functionally by its ability to bind HAS and another target, which can be any other type of molecule. 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". The claimed proteins are analogous to antibodies. 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., TNFα) is not in and of itself sufficient to provide a description of the genus of proteins binding to said target.
The prior art appreciates that "Mutations … are generally destabilizing, and can reduce protein … fitness" and "In general, more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation" (pg 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). The prior art also appreciates that "the range of possible SNV [single nucleotide variation] effects at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge" (pg 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed). Thus, knowledge of the sequence of a protein (e.g., SEQ ID NO: 1) is not sufficient for the skilled artisan at the time of the effective filing date to predict which substitution mutations will result in a protein having the required target activity.
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).
A description of a single species that is defined by its amino acid sequences is not representative of a genus encompassing thousands or more members having different structures. 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 the instant case, the specification provides very limited guidance as to the nature of which members of the vast genus of amino acid sequences encompassed by claim 1 that will have the required functionality. The working examples, starting at ¶ 88, provide the amino acid sequence of 12 examples of mutated proteins are demonstrated to retain binding to HSA and also bind to one of 7 other targets (Table 3). Thus, for each target, the specification provides 2-4 examples of species that are encompassed by the genus of claims. These examples were identified by screening a phage display library (¶ 91). While the identified sequences meet the written description requirement, the sequences do not provide any description of other sequences in the vast genus of encompassed structures that also have the required functionality in binding to a particular target.
Furthermore, these exemplary mutated proteins do not include variation at the 14 other positions of SEQ ID NO: 1 that tolerated change, and the specification does not provide corresponding examples where these positions, either singly or in combination, are filled with amino acids corresponding to the encompassed range (i.e., all 20 amino acids) and still retain binding to HSA.
The specification does not provide sufficient description to identify a representative number of species encompassed by the claimed genus by any method other than screening for additional members. However, as with antibodies, adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
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 bispecific protein capable of binding HAS and TNFα (or another target specified in Table 4), comprising a sequence disclosed in Table 4, 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).
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