DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
The amendment of 27 April 2026 has been entered in full. Claims 1, 2, 12, 15, 16, 18-21, 23, 33, 35-37, 39, 41, 45, and 46 are amended. Claims 3-9, 11, 13, 14, 17, 25, 27, 29, 31, 32, 34, 38, 40, 42, and 47-101 are cancelled.
It is noted that claims 45 and 46 were previously withdrawn from consideration as being drawn to a non-elected invention (see page 2 of the previous Office Action of 27 January 2026).
However, claims 45 and 46 have been amended in the amendment of 27 April 2026 to recite a pharmaceutical composition, rather than a method. Therefore, claims 45 and 46 are being rejoined to the examined claims of Group I.
It is noted to Applicant that if any of the currently examined claims are amended to recite a method or if any new claims are introduced that are directed to a method, such claims will be withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention if there is no allowable generic or linking claim.
Claims 1, 2, 10, 12, 15, 16, 18-24, 26, 28, 30, 33, 35-37, 39, 41, and 43-46 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 19 March 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The replacement drawings were received on 27 April 2026. These drawings are acceptable.
Withdrawn Objections and/or Rejections
1. The objections to the drawings as set forth at pages 2-4 of the previous Office Action of 27 January 2026 are withdrawn in view of the submission of replacement drawings (27 April 2026).
2. The Sequence Listing Requirement deficiencies set forth at pages 4-7 of the previous Office Action of 27 January 2026 are withdrawn in view of Applicant’s amendment to the instant specification and submission of a replacement sequence listing (27 April 2026).
3. The objections to the specification as set forth at page 8 of the previous Office Action of 27 January 2026 are withdrawn in view of the amended specification (27 April 2026).
4. The objections to claims 17, 23, 36, 41, and 57 as set forth at pages 8-9 of the previous Office Action of 27 January 2026 are withdrawn in view of the amended and cancelled claims (27 April 2026).
5. The rejections of claims 12, 20, 26, 28, 30, 33, 35, 37, 39, and 41 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth at pages 9-12 of the previous Office Action of 27 January 2026 are withdrawn in view of the amended claims (27 April 2026).
6. The rejection of claim 26 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as set forth at pages 12-13 of the previous Office Action of 27 January 2026 is withdrawn in view of the amended claim (27 April 2026).
7. The rejection of claims 1, 7, 16, 17, 24, 26, and 37 under 35 U.S.C. 102(a)(1) as being anticipated by Burkart et al. (WO 2020/023918, published 30 January 2020) as set forth at pages 22-24 of the previous Office Action of 27 January 2026 is withdrawn in view of the amended and cancelled claims (27 April 2026). Specifically, Burkart et al. do not teach a polypeptide comprising a b1 domain of neuropilin, wherein the b1 domain is the amino acid sequence of SEQ ID NO: 4 or 5.
8. The rejection of claims 1, 7, 16, 24, 37, 41, 43, 44, and 72 under 35 U.S.C. 102(a)(1) as being anticipated by Sapieha et al. (US 2017/0283502) as set forth at pages 25-27 of the previous Office Action of 27 January 2026 is withdrawn in view of the amended and cancelled claims (27 April 2026). Specifically, Saphieha et al. do not teach a polypeptide comprising a b1 domain of neuropilin, wherein the b1 domain is the amino acid sequence of SEQ ID NO: 4 or 5.
New 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.
9. Claims 1, 2, 10, 12, 15, 16, 18-24, 26, 28, 30, 33, 35-37, 39, 41, and 43-46 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
9a. Claims 1, 2, 10, 12, 15, 16, 18-24, 26, 28, 30, 33, 35-37, 39, 41, and 43-46 are rejected as being indefinite because it is not clear what the difference is between the b1 domain of a neuropilin and the variant of the b1 domain. More specifically, claim 1, lines 6-7 recites that the b1 domain is an amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A). However, claim 1, lines 8-9 also recites that the variant of the b1 domain comprises an amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A). Therefore, the b1 domain and the variant of the b1 domain comprise the same exact sequences. These limitations are confusing to one of ordinary skill in the art.
Please note that this issue could be overcome by amending claim 1 to remove reference to the variant b1 domain (since SEQ ID No. 4 and 5 are already variant sequences). For instance:
“A polypeptide comprising (a) a b1 domain of a neuropilinthe amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A),
9b. Claims 20 and 21 are rejected as being indefinite because claim 20 recites the human ACE2 domain of SEQ ID NO. 34 contains a mutation at a position selected from the group consisting of F28, D30, and L79. However, the amino acid sequence of SEQ ID NO: 34 is only 23 amino acids in length. Therefore, it is not clear what “F28, D30, and L79” positions claim 20 is referring to.
Additionally, in claim 21, the amino acid sequences of SEQ ID NOs: 40 and 42 are only 72 amino acids in length. Therefore, it is not clear how “L79” (from claim 20) relates to these sequences. Lastly, the amino acid sequences of SEQ ID NOs: 40-43 do not have a “F28”, “D30”, or “L79”. Are these amino acid positions already mutated in SEQ ID NOs: 40-43? Or, are these amino acid positions located somewhere else within the sequences?
New 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 pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
10. Claims 12, 35, and 36 are 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.
(a) Claim 12 recites the polypeptide of claim 1, wherein the b1 domain, or variant of the b1 domain, comprises a mutation that enhances the affinity for an S protein of COVID-19 when compared with the unmutated human NRP1 b1 domain of SEQ ID NO. 3, and wherein the mutation is at a position selected from the group consisting of E319 and K351.
However, claim 1, from which claim 12 depends recites that the b1 domain is an amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A) and that the variant of the b1 domain comprises an amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A) (emphasis added by Examiner). Claim 1 clearly recites that the b1 domain (and variant thereof) comprise specific amino acid sequences that comprise either E319A or K351A. Therefore, claim 12 does not further limit claim 1 and fails to include all of the limitations of claim 1.
(b) Claim 35 recites the polypeptide of claim 2 with specific configurations, wherein b1b2 is a b1b2 domain of neuropilin selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14.
However, several of these amino acid sequences recited in claim 35 fail to include the NRP1 b1 domain limitations as recited in claims 1 and 2 (from which claim 35 depends).
The amino acid sequence of SEQ ID NO: 7 is NRP1 b1b2 (with no E319A or K351A mutation) (see page 35 of the instant specification of 27 April 2026).
The amino acid sequence of SEQ ID NO: 10 is NRP1 b1b2-Y297A/S346A/Y353A (with no E319A or K351A mutation) (see page 35 of the instant specification of 27 April 2026).
Lastly, the amino acid sequences of SEQ ID NOs: 12-14 are directed to NRP2 b1b2 sequences (and not directed to NRP1 or E319A or K351A mutations).
Therefore, the amino acid sequences of SEQ ID NOs: 7, 10, 12, 13, and 14 as recited in claim 35 fail to include the neuropilin domain limitations as recited in claims 1 and 2 (i.e., the amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A)).
(c) Claim 36 recites the polypeptide of claim 2, wherein the polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID. NOS: 90-112.
However, several of these amino acid sequences recited in claim 36 fail to include the NRP1 b1 domain limitations as recited in claims 1 and 2 (from which claim 36 depends).
First, it is noted that the amino acid sequences of SEQ ID NOs: 90-112 are also provided as construct numbers 37-59 (see Table 8B, pages 67-76 of the instant specification of 27 April 2026). Table 8A (at pages 62-64 of the specification) describes the components of each specific construct. However, constructs 37-40, 46-53, 56, 58, and 59 (SEQ ID NOs: 90-93, 99-106, 109, 111, and 112) do not comprise NRP1 b1 E319A (SEQ ID NO: 4) or NRP1 b1 K351A (SEQ ID NO: 5).
Second, construct 45 (SEQ ID NO: 98) comprises a b1b2 of NRP2 and does not comprise NRP1 b1 E319A (SEQ ID NO: 4) or NRP1 b1 K351A mutation (SEQ ID NO: 5).
Therefore, the amino acid sequences of SEQ ID NOs: SEQ ID NOs: 90-93, 98-106, 109, 111, and 112 as recited in claim 36 fail to include the neuropilin domain limitations as recited in claims 1 and 2 (i.e., the amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A)).
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.
New Claim Rejections - 35 USC § 112(a)
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.
11. Claims 45 and 46 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 45 is directed to a pharmaceutical composition for preventing COVID infection comprising a polypeptide of claim 1 as active.
Claim 46 is directed to a pharmaceutical composition for treating COVID infection comprising a polypeptide of claim 1 as active ingredient.
The specification of the instant application teaches that the present disclosure provides a method of reducing COVID infection; a method of treating a subject suffering from COVID infection; and a method of preventing COVID infection, the method comprising the administration of the polypeptides disclosed herein to a subject in need thereof (page 5, [15-19]). The specification discloses that a SARS-CoV-2 virus can enter and infect a human cell by attaching its spike protein to an angiotensin converting enzyme 2 (ACE2) receptor that residues on the surface of the cell (page 27, [140]). The specification states that once the spike protein is bound to the ACE2 receptor, the SARS-CoV-2 can enter the cell where the virus shell is broken apart, releasing RNA into the host cell where it replicates and generate more viral particles (page 27, [140]). The specification teaches that neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway in the central nervous system (page 28, [143]). The specification indicates that the soluble domains of the SARS-CoV-2 utilize the binding ability of the b1b2 domain of a neuropilin-1 receptor and the soluble ACE2 receptor and that by designing the Fc domain of the immunoglobulin to provide a double decoy soluble protein, the corresponding fusion polypeptide can effectively bind spike proteins of one or more SARS-CoV-2 virus particles (page 28, [143]; page 29, [145]). The specification states that an E319A mutation of the neuropilin b1 domain has a stronger binding affinity to VEGFA with heparin while the K351A mutation of the b1 domain has a weaker binding affinity to VEGFA w/ or w/o heparin (page 31, [156]).
The specification discloses that the amino acid construct of SEQ ID NO: 139, for example, has the structure of b1b2-b1b2-Fc (with E319A mutation), has increased VEGF binding, and binds to SARS-CoV-2 (page 182, Example 17). In Example 10 of the instant specification, the polypeptide of SEQ ID NO: 122 (b1b2-Fc, wild-type NRP1) is administered to SARS-CoV-2 hamsters (pages 120-126, arms 4 and 5; pages 161, Table 22). The results of Experiment 10 indicate that the beneficial effects seen with SEQ ID NO: 122 and SAD35 (an anti-SARS-CoV-2 RBD Neutralizing Antibody, Human IgG1)) in plethysmography data do not seem to correlate with the degree of inflammation seen histologically (page 126, [478]). The specification also states that the small, but significant, beneficial effects of the treatments may have been muted since the pharmacokinetics of SEQ ID NO: 122 and SAD35 in the hamster are not known (page 126, [479]). Furthermore, the specification teaches that analysis of BAL fluid for SARS-CoV-2 nucleocapsid gene targets per microliter of RNA isolated from by RT-qPCR show no significant difference between the titer of viral challenge with PBS vs. SEQ ID NO: 122 or SAD35 treatment (page 126, [480]).
In Example 11, the polypeptides of SEQ ID NO: 122, SEQ ID NO: 154 (b1b2-Fc, wild-type NRP2), and SEQ ID NO: 192 (b1b2-Fc-ACE2-1; NRP1) are administered to SARS-CoV-2 hamsters (pages 127-132, arms 3-5; pages 164-165). The specification teaches that treatment of hamsters with any of the three compounds decreased IFNγ level when compared with viral controls (but statistical difference could not be determined due to small group size and variability measurements) (page 132, [516]). Plethysmography data shows that SEQ ID NO: 122 and SEQ ID NO: 192 help the hamsters achieve respiration closer to the normal when compared to media control and virus control groups (page 132, [516]). The specification discloses that viral titers in olfactory bulb lingered at higher values in SEQ ID NO: 192 treated hamsters on day 7 when compared with viral controls and SEQ ID NO: 122 or SEQ ID NO: 154, but that viral titers on day 4 were diminished in treatment groups when compared viral controls (page 132, [516]). Lastly, the specification states that treatment with SEQ ID NO: 122 and to a greater extent, SEQ ID NO: 192, kept the Ang II/Ang 1-7 ratio normal or improved, when compared to virus control, albeit without apparent decrease in pulmonary inflammation (page 132, [517]).
In Example 12 of the specification, the polypeptide of SEQ ID NO: 113 (b1-Fc, WT NRP1) is administered to K18-ACE2 (JAX) mice after SARS-CoV-2 challenge (pages 132-136, arm 1; page 160). The specification states that the “body weights and clinical scores of SEQ ID NO: 113 did not differ significantly from the virus infected control group” (page 136, [543]). The specification also teaches that serum levels of D-dimer were not statistically different between placebo and viral controls or the SEQ ID NO: 113 and anti-SARS-CoV-2 spike protein antibody treatment groups (page 136, [544]).
Regarding instant claim 45, it is noted that the Examiner has interpreted the phrase “for preventing COVID infection” as an intended use of the claimed pharmaceutical composition. The instant specification teaches that the terms "prophylaxis" or "prophylactic use" and "prophylactic treatment" as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease (page 20, [116]). The specification continues to disclose that terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease (page 20, [116]). Thus, “preventing” is interpreted by the Examiner as meaning that an activity will not occur, i.e. COVID infection will not occur.
However, there are no methods or working examples in the instant specification that indicate prevention of COVID infection by administration of the claimed NRP1 b1 domain-immunoglobulin domain polypeptide constructs. Additionally, the totality of the methods and working examples in the instant specification (as highlighted directly above) seem to indicate there is no significant, beneficial effects of the NRP1 b1-Fc; NRP1 b1b2-Fc; and NRP1 b1b2-Fc-ACE2-1 constructs to even treat COVID infection. Therefore, undue experimentation would be required of the skilled artisan to determine the quantity of the NRP1 b1 domain-immunoglobulin domain polypeptide constructs to be administered and the duration of administration to prevent or treat COVID infection. The limited teachings of the specification are not adequate guidance, but are merely an invitation for the artisan to use the current invention as a starting point for further experimentation. The claimed polypeptide constructs may not necessarily treat or prevent COVID infection.
The skilled artisan would also not be able to predict that administration of the claimed NRP1 b1 domain-immunoglobulin domain polypeptide constructs would treat or prevent COVID infection. The instant specification states that, “[t]here are currently no vaccines nor specific antiviral treatments for COVID-19” (page 2, [7]). The courts have stated that patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be patentable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. Reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genentech v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 (1997). Furthermore, Applicant is reminded that a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 634, 38 USPQ 189, 191 (CCPA 1938; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Due to the large quantity of experimentation necessary to treat and prevent COVID infection by administration of the claimed NRP1 b1 domain-immunoglobulin domain polypeptide constructs; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; and the unpredictability of treating and preventing COVID infection, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Maintained Claim Rejections - 35 USC § 112(a)
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.
12. Claims 1, 2, 10, 12, 15, 16, 18-24, 26, 28, 30, 33, 35, 37, 39, 41, and 43-46 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The basis for this rejection is set forth at pages 13-22 of the previous Office Action of 27 January 2026.
Amended claim 1 is directed to a polypeptide comprising (a) a b1 domain of a neuropilin, or a variant of the b1 domain having an alteration, variation, or modification in its sequence; and (b) an immunoglobulin domain, wherein the b1 domain is an amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A), and wherein the variant of the b1 domain comprises an amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A), and wherein the b1 domain is capable of specifically binding to a coat protein of a virus selected from the group consisting of coronaviridae, herpesviridae, and retroviradae.
Instant claim 2 recites that the polypeptide of claim 1 further comprises a human ACE2 domain comprising an amino acid sequence of SEQ ID NO: 34, or a variant of the ACE2 domain having an alteration, variation, or modification in its sequence, or a fragment of the ACE2 domain.
Amended claim 41 recites the polypeptide of claim 1, further comprising a signal peptide, and wherein the signal sequence comprises an amino acid sequence of SEQ ID NO. 53.
(i) At page 11 of the Response of 27 April 2026, Applicant submits that amendments to claims 1 and 2 overcome the rejection. Applicant argues that the amino acid sequence of SEQ ID NO: 4 (NRP1 b1 E319A) and SEQ ID NO: 5 (NRP1 b1 K351A) are disclosed in Table 1 ([0163-0164]). Applicant states that the human ACE2 domain of SEQ ID NO: 34 is fully disclosed in Table 3 (pages 44-46 of the specification).
Applicant’s arguments have been fully considered but are not found to be persuasive. Claims 1, 2 and 41 recite the phrase “an amino acid sequence of” and thus, is broadly interpreted by the Examiner as reading upon fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NOs: 4, 5, 34, and 53. Claim 2 also still recites “or a variant of the ACE2 domain having an alteration, variation, or modification in its sequence, or a fragment of the ACE2 domain”.
However, the specification does not teach any fragments, alterations, variations, and/or modifications of the amino acid sequences recited in the instant claims, other than the full-length amino acid sequences of SEQ ID NOs: 4, 5, 34, and 53. The claims are drawn to a genus of fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4, 5, 34, and 53.
There is no identification of any particular structure or component of the neuropilin b1 domain or variant of the b1 domain; ACE2 domain or variant of the ACE2 domain; or signal peptide sequence that must be conserved in order to provide the required function of binding to a coat protein of a virus selected from the group consisting of coronaviridae, herpesviridae, and retroviradae (see for example, claims 1, 5, and 59). Therefore, the claims are drawn to a genus of neuropilin b1 fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4 and 5; a genus of ACE2 domain fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 34; and a genus of signal peptide fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 53.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the only factors present in the claims are (1) structural requirements that the polypeptide comprises neuropilin b1 fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4 and 5; ACE2 domain fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 34; and signal peptide fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 53; and (2) a functional requirement of binding to a coat protein of a virus selected from the group consisting of coronaviridae, herpesviridae, and retroviridae. There is no identification of any particular sequence or structure of a neuropilin b1 domain fragment, alteration, variation, and/or modification of the amino acid sequences of SEQ ID NO: 4 and 5; an ACE2 domain fragment, alteration, variation, and/or modification of the amino acid sequence of SEQ ID NO: 34; and a signal peptide fragment, alteration, variation, and/or modification of the amino acid sequence of SEQ ID NO: 53 that must be conserved in order to provide the required function of binding to a coat protein of a virus. Thus, the claims are drawn to a genus of neuropilin b1 fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4 and 5; a genus of ACE2 domain fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 34; and a genus of signal peptide fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 53.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of (i) the genus neuropilin b1 fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4 and 5; (ii) the genus of ACE2 domain fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 34; and (iii) the genus of signal peptide fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 53; and the function of binding to a coat protein of a virus. In other words, the specification does not teach the structure which results in a polypeptide comprising neuropilin 1, ACE2 domains, and signal peptides with the claimed required characteristics. The description in the prior art and the specification of the full-length NRP1 and NRP2 sequences; full length NRP1 and NRP2 b1 and b2 domains; NRP1 and NRP2 b1/b2 domains with specific substitutions (pages 34-38 of instant specification); specific ACE2 domains (pages 44-47 of instant specification); specific signal sequence (page 48, Table 5); and full length polypeptide amino acid sequences of SEQ ID NOs: 113-116, 121-122, 133-137, 148-149, 154, 162, and 193-201 are not adequate written description of an entire genus of (i) the neuropilin b1 fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4 and 5; (ii) the ACE2 domain fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 34; and (iii) the signal peptide fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 53.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations 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 (p. 18). Furthermore, Herzog et al. (Mol Bio Cell 22: 2766-2776, 2011) teach that mutations in the NRP1 b1 domain (Y297A and D320A) result in complete loss of VEGF binding to NRP1 (abstract; page 2767, entire column 1 through page 2770, top of column 1). Geretti et al. also teach that exchange of electronegative residues in b1b2 NRP2 to neutral ones (E284A, E291A) show a 2-fold reduced affinity for VEGF binding (J Biol Chem 287(35): 25698-25707, 2007; page 25699, top of column 1; abstract; page 25702, column 2; Table 2). Conversely, increasing the electronegative potential in b1b2 NRP2 (R287E, N290S/D) increases affinity for VEGF binding by 8-fold (Geretti et al., page 25699, column 1; page 25702, column 2; Table 2).
Applicant is reminded that 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 (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “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” (See page 1117). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of (i) the genus of neuropilin b1 fragments, alterations, variations, and/or modifications of the amino acid sequences of SEQ ID NO: 4 and 5; (ii) the genus of ACE2 domain fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 34; and (iii) the genus of signal peptide fragments, alterations, variations, and/or modifications of the amino acid sequence of SEQ ID NO: 53 of the encompassed claims, 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 specific neuropilin b1 domain, ACE2 domain, and signal peptide are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
Please note that this issue could be overcome by:
(a) amending claim 1 to recite “..the b1 domain is (or, comprises) the amino acid sequence of SEQ ID NO. 4 (NRP1 b1 E319A) or SEQ ID NO. 5 (NRP1 b1 K351A)”;
(b) amending claim 2 to recite “…ACE2 domain comprising the amino acid sequence of SEQ ID NO: 34” and removing variant and fragment limitations; and
(c) amending claim 41 to recite “…the signal peptide comprises the amino acid sequence of SEQ ID NO. 53”.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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BEB
Art Unit 1647
07 July 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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