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 10/22/25 has been entered in full. Claims 1-10 are amended. Claims 11-17 and 19-20 are canceled. Claims 1-10 and 18 are pending.
Election/Restrictions
A restriction requirement was mailed on 8/22/25. Applicants' election without traverse of Invention I, currently claims 1-10 and 18, in the reply filed on 10/22/25 is acknowledged. The claims directed to non-elected Invention II have been canceled.
The election without traverse of an antibody comprising HCVR/LCVR of SEQ ID NO: 2/10 as the species of antibody in the reply filed on 10/22/25 is also acknowledged. The claims as amended are limited to the elected species.
Claims 1-10 and 18 are under consideration.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because, in part, is directed to “Uses Thereof”, but the claims are limited to antibodies, which are products. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “ANTI-NPR1 ANTIBODIES”.
Appropriate correction is required.
Claim Objections
Claims 4 and 10 are objected to because of the following informalities:
In claim 4, lines 4-5, “SEQ ID NOs: 6” and “SEQ ID NOs: 8” should be “SEQ ID NO: 6” and “SEQ ID NO: 8”, respectively.
In claim 4, line 6, the LCDR of “SEQ ID NO: 14” should be replaced with the amino acid sequence “VAS”. See Table 1 of the specification on page 44, where the LCDR2 of mAb22033 is “VAS” rather than SEQ ID NO: 14. Under the ST.26 sequence rules, sequences of three or less amino acids are excluded from the sequence listing, and thus SEQ ID NO: 14 in the current sequence listing is an empty sequence (“000”).
In claim 10, each dissociation constant should be written with a space between the number and the units; e.g., on line 4, “690nM” should be “690 nM”. The following instances should be corrected: “690nM” (line 4), “42nM” (line 6), “80nM” (line 8), “20nM” (line 9), “365nM” (line 11), “30nM” (line 12)”, “10nM” (line 14), “10nM” (line 15”), “5nM” (line 17) and “385nM” (line 18).
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 1-10 and 18 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.
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.
Claim 1 is directed to an isolated antibody, or antigen-binding fragment, that binds specifically to the protein NPR1 (natriuretic peptide receptor 1), and comprises three heavy chain (HC) complementarity-determining regions (CDRs) contained within a heavy chain variable region (HCVR) having at least 95% sequence identity to SEQ ID NO: 2 and three light chain (LC) CDRs contained with a light chain variable region (LCVR) having at least 95% sequence identity to SEQ ID NO: 10. Dependent claims 2 and 3 further limit the HCVR (claim 2) or LCVR (claim 3) to having at least 95% to SEQ ID NO: 2 or 10, respectively. Claim 4 further limits the antibody to one comprising CDRs having “an amino acid sequence” of SEQ ID NO: 4, 6, 8, 12, 14 and 16, and claim 5 further limits this antibody to one having an HCVR/LCVR pair that is at least 95% identical to SEQ ID NO: 2/10. Claims 6-8 further limit the antibody by defining the portion of the extracellular domain (ECD) of NPR1 that the antibody interacts with. Claim 9 limits the antibody of claim 6 to a fully human monoclonal antibody. Claim 10 further limits the antibody to one having a further property selected from a group of fourteen different recited properties. Claim 18 is directed to a pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or diluent.
The claims encompass a genus of antibody structures because they are not limited to a single defined antibody structure. Claim 1 encompasses an antibody having the CDRs found in an antibody having sequences that are 95% identical to the heavy and light chain sequences of SEQ ID NO: 2 and 10. The heavy chain sequence of SEQ ID NO: 2 is 124 amino acids in length, and thus the sequences that are at least 95% identical include those with up to 6 amino acid changes in the sequences. The HCDRs found within SEQ ID NO: 2 are 8 (SEQ ID NO: 4 and 6) or 17 (SEQ ID NO: 8) amino acids in length. The genus of variants include those in which up to 6 amino acids have been changed in one of these CDRs, which represents 75% (SEQ ID NO: 4 or 6) or 35% (SEQ ID NO: 8) of one of the CDRs. Likewise, the light chain sequence of SEQ ID NO: 10 is 106 amino acids in length, and thus the sequences that are at least 95% identical include those with up to 5 amino acid changes in the sequences. The LCDRs found within SEQ ID NO: 10 are 6 (SEQ ID NO: 12), 3 (LCDR2) or 8 (SEQ ID NO: 16) amino acids in length. The genus of variants include those in which up to 6 amino acids have been changed in one of these CDRs, which represents 83% (SEQ ID NO: 12), 100% (LCDR2) or 62.5% (SEQ ID NO: 8) of one of the CDRs. Thus, the genus of antibodies encompassed by claim 1 includes variants in which a significant portion, in some cases a majority, of one of the CDRs is different from those of the reference sequences of SEQ ID NO: 2 or 10.
While the general structure of an antibody is well-known in the art, the structure of the portion of an antibody that provides its functionality, i.e., the ability to bind to a particular antigen, is not. The antigen-binding site is formed by the association of the heavy and light chain variable regions, which each have three CDRs that provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the immunoglobulin. Furthermore, the set of CDRs in one antibody is independent of the set found in each other antibody, and thus knowledge of one set of CDRs does not provide any predictable information about other sets of CDRs that provide binding specificity, even with regard to the same antigen. 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 a binding target itself, e.g. the ECD of NPR1, or a fragment or region or subsequence thereof, is not sufficient to provide a written description of the genus of the antibodies that bind to said target. Instead, a description of the antibody structures corresponding to the claimed genus is required.
The reference of Benjamini, 1991, teaches that an epitope to which an antibody binds is approximately equivalent to 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only; cite don the 9/4/24 IDS). Even considering only continuous epitopes, the extracellular domain (ECD) of NPR1, which consists of 318 amino acids (residues 29-347 of SEQ ID NO: 194), comprises numerous sets of five amino acids that can serve as epitopes (e.g., residues 29-33, 30-34, 31-35, 32-36, 33-37, etc, up to residues 343-347). Different antibody structures will bind to each of these different epitopes. Ferrara et al (2015. mAbs. 7(1): 32-41; cited on the 9/4/24 IDS) teach that there is substantial variation in the genus of antibodies that bind to a single immunogen, 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 exists a large number of different antibody structures that will specifically bind to the ECD of NPR1, and these structures are not described by the structure of NPR1 alone.
In support of the claimed genus of antibodies, the specification discloses an antibody comprising the HCDRs 1-3 of SEQ ID NO: 2, 4 and 6, and the LCDRs 1-3 of SEQ ID NO: 12, VAS and 16 as mAb22033 (Table 1, page 44). The specification further teaches that this antibodies binds to the ECD of both human and monkey NPR1, in the presence and absence of ANP or BNP (¶ 190-192), and is an agonist antibody, activating NPR1 (Table 29, ¶ 204). While this set of CDR sequences is sufficient to provide written description for an antibody comprising this set of CDRs (e.g., an antibody comprising the amino acid sequences of SEQ ID NO: 4, 6, 8, 12, VAS and 16), this set of CDRS to describe the full genus of antibodies of the claims, which include variant CDR sequences. The specification provides no examples of antibodies comprising CDR variants of SEQ ID NO: 4, 6, 8, 12, VAS or 16 that retain the ability to bind to NPR1.
Dependent claim 4 is included in this rejection because it uses the language “an amino acid sequence of SEQ ID NO: X”, which broadly encompasses any sequence of two amino acids found within the reference sequence. For example, “an amino acid sequence of SEQ ID NO: 4” encompasses any two consecutive amino acids selected from the eight amino acids of SEQ ID NO: 4. In order to limit the antibody of claim 4 to one that comprises each of the CDRs in its entirety, the claim would need to be amended to recite “the amino acid sequence of SEQ ID NO: X”
MPEP 2163 provides guidance for complying with the written description requirement of 35 U.S.C. 112(a) that the “specification shall contain a written description of the invention…”; this requirement is separate and distinct from the enablement requirement (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). Written description for a claimed genus may 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 written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Written description for a claimed genus can also be satisfied when relevant identifying characteristics are disclosed. Per MPEP 2163:
“[d]etermine whether the specification discloses other 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. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.”
However, claiming by function does not necessarily satisfy the requirement:
“[A] generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA," without more, is not an adequate written description of the genus because it does not distinguish the claimed genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others … A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. It is only a definition of a useful result rather than a definition of what achieves that result” (Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)).
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)), and “[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).
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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-NPR1 antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. 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). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only
An isolated antibody, or antigen-binding fragment thereof, that binds specifically to natriuretic peptide receptor 1 (NPR1) protein, wherein the antibody, or antigen-binding fragment thereof, comprises
(a) a HCDR1 having the amino acid sequence of SEQ ID NO: 4;
(b) a HCDR2 having the amino acid sequence of SEQ ID NO: 6;
(c) a HCDR3 having the amino acid sequence of SEQ ID NO: 8;
(d) a LCDR1 having the amino acid sequence of SEQ ID NO: 12;
(e) a LCDR2 having the amino acid sequence of VAS; and
(f) a LCDR3 having the amino acid sequence of SEQ ID NO: 16, but not the full breadth of the claims, meet 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).
Double Patenting
The nonstatutory double (NSDP) patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A NSDP rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer (TD) in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on NSDP provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A TD must be signed in compliance with 37 CFR 1.321(b).
The filing of a TD by itself is not a complete reply to a NSDP rejection. A complete reply requires that the TD be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains TD forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer (eTD) may be filled out completely online using web-screens. An eTD that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTDs, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-10 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,306,148, issued 4/19/22 (cited on the 9/4/24 IDS), and which shares the same applicant and inventors with the instant application. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The instant application claims priority as a continuation to application 18/485,241 (now abandoned), which in in turn claims priority as a continuation to application 17/692,084, which in turn claims priority as a continuation to application 16/657,000, which issued as the ‘148 patent.
Instant independent claim 1 encompasses an isolated antibody or antigen-binding fragment that binds specifically to natriuretic peptide receptor 1 (NPR1) protein, wherein the antibody comprises HCDR1-3 contained with a heavy chain variable region (HCVR) comprising an amino acid sequence at least 95% identical to SEQ ID NO: 2, and comprises LCDR1-3 contained within a light chain variable region (LCVR) comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10. Claim 1 of ‘148 is directed to an antibody or antigen-binding fragment that specifically binds to NPR1 and comprises the HCDR1-3 of SEQ ID NO: 2 and the LCDR1-3 of SEQ ID NO: 10. As such, instant claim 1 fully encompasses the claim 1 of ‘148, and as such the claims ‘148 anticipate the instant claims, and the two sets of claims are therefore not patentably distinct.
Instant claims 2-10 and 18 depend from claim 1 and each further limit the method of claim 1 embodiments that correspond to the further limitations of the antibody of the dependent claims of ‘148 in the following manner:
Instant Claim
Claim of ‘148
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
10
18
11
As such, the antibody or antigen-binding fragment of instant dependent claims 2-10, and the composition of instant dependent claim 18, are anticipated by the corresponding claims of the ‘148 patent, and as such these instant claims are also not patentably distinct from the claims of ‘148.
Notes on Patentability
No prior art has been identified that teaches or renders obvious the amino acid sequence of the antibody identified as mAB22033 (Table 1, page 3), which comprises the HCVR having the amino acid sequence of SEQ ID NO: 2 and the LCVR having the amino acid sequence of SEQ ID NO: 10, and the HCDRs of SEQ ID NO: 2, SEQ ID NO: 4 and SEQ ID NO: 6, and the LCDRs of SEQ ID NO: 12, VAS, and SEQ ID NO: 16.
The instant application claims priority as a continuation to three parent applications:
---18/485,241, filed 10/11/23, and abandoned without a patent issuing.
---17/692,094, filed 3/10/22, from which issued patent 11,820,826 on 11/1/23.
The claims of the ‘826 patent are directed to polynucleotides, and correspond to the subject matter of non-elected Invention II in the original restriction requirement mailed on 12/16/20 in parent application 16/657,000. The instant claims are directed to antibody, and correspond to Invention I of the original restriction requirement. Thus, per MPEP 804.1, a non-statutory double patenting rejection of the instant claims over those of the ‘826 patent is prohibited by 35 U.S.C. 121.
---16/657,000, filed 10/18/19, from which issued patent 11,306,148 on 4/19/22. The claims of the ‘148 patent are directed to antibodies, and correspond to the subject matter of elected Invention I of the original restriction requirement mailed on 12/16/20 in the ‘000 application. A double patenting rejection of the instant claims over the claims of the ‘148 patent is set forth above.
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