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 .
DETAILED ACTION
This application is a US national phase of PCT/US2021/017305, filed February
10, 2021, with provisional application 62/976344 filed February 13, 2020.
Applicant's amendment filed June 6, 2025 is acknowledged. Claims 2, 4, 6, 11-13, 15-16, 21-23, 29, and 33-37 are canceled, and claims 38-39 are newly added. Claims 1, 3, 5, 7-10, 14, 17-20, 24-28, 30-32, and 38-39 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I and species: IgG1, SEQ ID NO: 15, SARS-CoV-2, “a peptide bond”, remdesvir, “a quantum dots”, in the reply filed on June 6, 2025 is acknowledged. Newly added claims 38-39 belong in Group I.
Claims 24-27 and 30-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 6, 2025. Currently claims 1, 3, 5, 7-10, 14, 17-20, 28, and 38-39 are under examination.
Claim Objections
Claims 3, 5, 7-10, 14, 17-20, 28, and 38-39 are objected to because of the following informalities:
Claims 3, 5, 7-10, 14, 17-18 recite a capitalized word “Claim 1” in the middle of a sentence.
Claim 19 recites a capitalized word “Claim 14” in the middle of a sentence.
Claim 20 recites a capitalized word “Claim 3” in the middle of a sentence.
Claim 28 recites a capitalized word “Claim 14” in the middle of a sentence.
Claim 38 recites abbreviations without their full names, ADCC, ADCP and CDC.
Claim 39 recites “nucleoid” is a typographical error for “nucleic”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 5, 7-8, 10, 14, 17-19, 28, and 38-39 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.
Claims 1, 3, 5, 7-8, 10, 14, 17-19, 28, and 38-39 recite a fusion protein comprising a variant angiotensin converting enzyme 2 (ACE2) domain covalently attached to a Fc domain, wherein the Fc lacks effector function, wherein the ACE2 domain comprises a N-terminal deletion, a C-terminal deletion, or both relative to a full-length wildtype ACE2 having a SEQ ID NO: 1, and the variant ACE2 domain has ACE2 activity. Claim 3 recites the variant ACE2 domain is SEQ ID NO: 3. Claims 5, 7-8, and 38 recite the Fc domain is selected from IgG1, inter alia; comprises a null mutation at K322A, L234A, or L235A compared to a wild type Fc domain SEQ ID NO: 5; the Fc domain comprises an amino acid sequence having 98% identity to SEQ ID NO: 6; or comprises an engineered hinge region with a C220S mutation or lacks ADCC, ADCP, & CDC. Claim 10 recites the variant ACE2 comprises an amino sequence having at least 98% identity to a segment of the wild-type ACE2 (SEQ ID NO: 1) between AA residues 1-17 and 615-740. The specification discloses in an embodiment the ACE2 variant domain has an amino acid sequence with at least 75%-99% sequence identity to SEQ ID NO. 1, and the Fc domain has an amino acid sequence with at least 75%-99% identity to SEQ ID NO: 6. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the specification merely gives working examples of six fusion protein combinations comprising two ACE2 variants (with various truncated sequence length identical to SEQ ID NO’s: 1 & 3), and the Fc domain comprising IgG1 null, IgG4, IgGA1, IgGA2 according to SEQ ID NO’s: 7, 9, 11, 13, 25, 15-19, 21 as disclosed on page 20, Sequence Listing, and are the only species whose complete structure is disclosed. Only the fusion protein SI-F019 (according to SEQ ID NO: 15) was tested for binding affinity to spikes, Fc receptors, and C1q, as shown in Tables 2 and 3, and only to SARS-CoV-2 and human FcγRs, C1q, and FcRn. While the genus encompasses a large number of variants that have the same activity as ACE2 and Fc domain in kind and the genus encompasses a large number of variants that have a different structure, the specification does not describe the complete structure of a representative number of species of the large genus of ACE2 variants or Fc domain variants, or functional equivalents thereof. Additionally, the specification does not describe the complete structure of a representative number of species of the large genus of fusion protein variants, only describing variant identity as being between 75-99% identical or similar to the protein of interest.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than nucleotide sequence or amino acid sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic of a ‘variant’ of ACE2 or Fc, is that the ACE2 domain has ACE2 activity, and the Fc domain lacks effector function, additionally the fusion protein has a binding affinity to SARS-CoV-2, SARS-CoV, or SARS spike protein. Such a broad limitation cannot be an identifying characteristic for the claimed diverse genus of variants since by Applicant’s definition of variant or functional equivalent thereof all members of the claimed genus will have that characteristic. Further, no identifying characteristics of the fusion protein variants are disclosed, only the variants outlined in the sequence listing on page 20.
The inventions of claims 14, 18-19, 28, and 39 require the use of the inventions of claims 1, 3, 5, 7-8, 10, 17, and 38, and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure of the species of fusion proteins comprising an ACE 2 variant domain covalently fused to a Fc domain of the claimed broad genus is not sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
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, 3, 5, 7-10, 14, 17-20, 28, and 38-39 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.
Claim 1 recites a fusion protein comprising a variant angiotensin converting enzyme 2 (ACE2) domain covalently attached to a Fc domain, wherein the Fc lacks effector function, wherein the ACE2 domain comprises a N-terminal deletion, a C-terminal deletion, or both relative to a full-length wildtype ACE2 having a SEQ ID NO: 1. It is unclear if the ACE2 domain is required to be similar or identical to SEQ ID NO: 1, and what would constitute a N- or C- terminal deletion, such as what amino acid residues would be involved, therefore the metes and bounds of this limitation is unclear. Furthermore it is unclear what ‘lacks effector function’ is referring to for the Fc domain, whether that be the Fc domain lacks binding effector function or triggering an effector functional response to the fusion protein, thus is indefinite.
Claim 5 recites the Fc domain is derived from an immunoglobulin selected from “…IgA1 (d-IgA1, S-IgA1)…”. It is unclear if the alternatives in the parentheses are both required, if any type of IgA1 is selected, or if only one or both can be selected.
Claim 7 recites “The fusion protein of Claim 1, wherein the Fc domain comprises a null mutation selected from K322A, L234A, and L235A compared to a wild type Fc domain having a SEQ ID NO: 5.”. Similarly to the rejection of claim 1 above, it is unclear if the Fc domain is required to be similar or identical to SEQ ID NO: 5, and it is further unclear what null mutations are required, as there are only 232 amino acids in SEQ ID NO: 5, which would inherently not encompass the recited mutations.
Claim 10 recites “The fusion protein of claim 1, wherein the variant ACE2 domain comprises an amino acid sequence having at least 98% sequence identity to a segment of amino acid sequence from the full-length wildtype ACE2, wherein the segment starts with an amino acid residue selected from residue 1-17 and ends with an amino acid residue selected from residue 615-740 of the full-length wild type ACE2.”. It is unclear what the metes and bounds of a ‘segment’ is, and if the amino acids ‘inside’ of the beginning and ending residues of each region range (i.e. 1-17 & 615-740) are required to be 100% identical to the wild type ACE2 (SEQ ID NO: 1), thus is indefinite.
Claim 38 recites: wherein the Fc domain comprises a Fc hinge region and the Fc hinge region is engineered to comprise a C220S mutation (EU numbering), or wherein the Fc domain lacks ADCC, ADCP and CDC. It is unclear what “EU numbering” in the parentheses is referring to, which SEQ ID NO: is the refence protein sequence for a C220S mutation, and what sequence and mutation(s) is correlated to the functional limitation that the Fc domain lacks ADCC, ADCP, and CDC.
Likewise claims 3, 8-9, 14, 17-20, and 39 are rejected as being dependent on an indefinite claim.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 5, 8, 10, 28, and 38 are rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Battle et al. (WO 2018/140456 A1, cited in PTO-892 mailed 12/06/2024, hereinafter “Battle”).
Regarding claims 1, 3, and 10, Battle teaches a fusion protein comprising a variant angiotensin converting enzyme 2 (ACE2) domain covalently fused to a Fc domain, wherein the variant ACE2 domain comprises a N-terminal deletion, a C-terminal deletion, or both, relative to a full-length wildtype ACE2 having a SEQ ID NO: 1 that has 100% sequence identity to instant SEQ ID NO’s: 1 & 3, wherein the variant ACE2 domain has ACE2 activity (para 72, 74, 67, 66).
Regarding claim 5, 8, and 38, Battle [0041] teaches the Fc portion of an antibody (constant fragment of human IgG) which preferably is devoid of its hinge region to prevent dimerization of the fusion polypeptide (e.g., SEQ ID NO:6), which has 98.4% identity to instant SEQ ID NO: 6 (See sequence comparison below).
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Regarding claim 28, Battle teaches the compositions disclosed herein may include pharmaceutical compositions comprising the presently disclosed bacterial toxins and formulated for administration to a subject in need thereof [0057].
Claims 1, 5, 10, 18, and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lei et al. (bioRxiv [Internet]. 2020 Feb 3; <doi.org/10.1101/2020.02.01.929976>, hereinafter “Lei”).
Lei teaches potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig (title). Lei teaches generation of a novel recombinant protein by connecting the extracellular domain of human ACE2 (aa 1-740) to the Fc region of the human immunoglobulin IgG1, wherein the ACE2 mutant has low catalytic activity, and expressed in the FreeStyle 293 expression system using vectors (pg. 5, para 3; abstract), thus anticipating claims 1, 5, 10, and 39.
Lei teaches both fusion proteins has high affinity binding to the receptor-binding domain (RBD) of SARS-CoV and 2019-nCoV and exerted desired pharmacological properties, moreover, fusion proteins potently neutralized SARS-CoV and 2019-nCoV in vitro (abstract). Lei teaches affinity measurement assays were performed with fusion proteins and CoV receptor binding domains (RBDs), thus inherently forming a protein complex as recited in claim 18 (pg. 6, para 1).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 as of the effective filing date of the claimed invention(s) 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 as of the effective filing date of the later invention 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.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Battle (WO 2018/140456 A1).
Battle [00132] teaches fusing the shortest ACE2 truncate to two considerably smaller polypeptides: a) monomeric soluble CH3 Fc domain and b) the albumin binding domain of the streptococcus G protein (ABD)]. A monomeric soluble CH3 Fc domain will be linked to c-terminus of the shortest ACE2 truncate through GS4 linker.
Battle does not explicitly teach a nucleic acid encoding a truncated ACE2-Fc.
However, Battle [00133] teaches an artificial gene encoding ABD035, a variant of ABD that has a highly improved albumin binding affinity (fM range) and inserting a flexible linker (G4S3) on the N-terminus of the ABD035 cDNA which will be genetically fused to the C terminus of short ACE2 cDNA to produce an ABD-fusion short ACE2 protein (ACE2-ABD). The genes encoding ACE2-ABD will be synthesized and cloned into pcDNA3 vector at the BamHI and Xhol sites and the expression and validation of the construct will be done as described in Aim 1; the ACE2-ABD (and alternatively ACE2-mCH3) will then be over expressed in mammalian cell lines [00133]. Thus, Battle suggests the recombinant production of fusion protein ACE2-mCH3 by the cloning of the encoding genes into a pcDNA3 vector and its expression in mammalian cells [00133].
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Battle’s gene cloning by replacing the ABD035 cDNA with the mCH3 cDNA to synthesize genes encoding truncated ACE2-mCH3, as suggested by Battle.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Battle (WO 2018/140456 A1) in view of Yang et al. (Frontiers in Immunology, 2018, vol. 8, art. 1860, pgs. 1-14, hereinafter “Yang”).
Battle teaches ACE2-Fc dimerizes through the hinge region of the Fc tag [0018] and that the Fc portion naturally exists as a dimer, bringing the total molecular weight of ACE2-Fc to 250 kDa [00132].
Battle does not teach a protein complex comprising the fusion protein, wherein two fusion proteins are paired through a disulfide bond.
However, Yang teaches engineering Fc fragments with optimized physicochemical properties, and that Fc plays multiple roles in dimerization for formation of Y-shaped structure of Ig and maintenance of the structure, and Fc-mediated effector functions and extension of serum half-life; there are two domains: second constant domain (CH2) and third constant domain (CH3) in monomeric Fc of IgG, wherein two CH3 domains interact strongly with each other to form homodimer resulting in dimerization of Fc (title, pg. 2, col. 2, para 1). Yang teaches CH3 also contains seven β-strands from A to G connected by three loops (loops BC, DE, and FG) and two helices (helix 1 and 2) with a native disulfide bond between strand B (C367) and F (C425) as CH2 (Figure 1), and by distinguishing from two CH2 domain with in Fc, two CH3 domains can interact with each other very strongly, which leads to the formation of dimeric Fc structure, probably due to the homo-interaction, resulting in a dimeric CH3 that has much higher stability than monomeric CH2 (pg. 4, col, 2, para 2). Amino acids at C-terminal of CH3 were replaced to introduction an additional inter-domain disulfide bond between two CH3 domains in Fc or dimeric CH3 or CH3 domain. And the conformational stability of both the CH2 and CH3 domain could be improved in an Fc variant with this kind of inter-domain disulfide bond (pg. 6. Last three sentences of the left column).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify an ACE2-Fc fusion protein comprising a recombinant CH3 domain, as taught by Battle, to form a complex of two ACE2-Fc fusion proteins when the Fc CH3 domains dimerize through introduced inter-domain disulfide bonds, as taught by Yang, with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to create such a protein complex wtih increased protein stability.
Claims 7, 9, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Battle as applied to claims 1, 3, 5, 8, 10, 28, and 38 above, and further in view of Moore et al. (Methods, 2019, 154, pgs. 38-50, cited in IDS filed 4/27/2022, hereinafter “Moore”).
Battle teaches the Fc region can be devoid of its hinge region (SEQ ID NO: 6), or a monomeric CH3 Fc derivative (SEQ ID NO’s 7 or 8) [0041]. Battle does not teach the specific mutations recited in claim 7, nor the specific sequences recited in claims 9 and 20.
However, Moore teaches a robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies, and teaches to further silence FcγR interaction, we engineered an IgG1 variant that combined the IgG2 lower hinge substitution with an additional CH2 substitution (S267K) at a surface residue previously shown to dramatically modulate FcγRII affinity; the FcγR binding of the resulting Fc variant mAb (E233P/ L234V/L235A/G236del/S267K) was compared to that of native IgG1 by surface plasmon resonance, and binding to Fcγ receptors I, IIa, IIb, and IIIa were not observed, and also established the silencing substitutions did not affect the thermostability of the CH2 region (pg. 45, col. 2, para 1, Fig. 7), which meets the limitation in claim 7.
Although Battle and Moore do not explicitly disclose the fusion protein sequence SEQ ID NO: 15 recited in claim 9 or the nucleic acid sequence SEQ ID NO: 8 recited in claim 20, as disclosed in the specification, SEQ ID NO: 15 comprises instant SEQ ID NO’s: 3 & 6, and SEQ ID NO: 8 encodes SEQ ID NO: 7 (which also encompass SEQ ID NO’s: 3 & 6), Battle teaches the truncated version of ACE2 (instant SEQ ID NO: 3) & Fc region (instant SEQ ID NO: 5), and Moore teaches the effects of null mutations (L235A) on silencing Fc binding affinity (the IgG1 Fc null SEQ ID NO: 6), it would be prima facie obvious to one of ordinary skill in the art before the effective filing date, to create a fusion protein covalently fusing these domains with the recited null mutations to arrive at the claimed invention.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Battle as applied to claims 1, 3, 5, 8, 10, 28, and 38 above, and further in view of Lei.
Battle teaches ACE2 is the cellular receptor for sudden acute respiratory syndrome (SARS) coronavirus/SARS-CoV and human coronavirus NL63/HCoV- NL63 [0043].
Battle does not teach the fusion protein’s binding affinity to SARS-CoV-2 with an equilibrium dissociation constant below 50nM.
However, Lei teaches potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig (title). Lei teaches generation of a novel recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1, wherein the ACE2 mutant has low catalytic activity (abstract). Lei teaches both fusion proteins has high affinity binding to the RBD of SARS-CoV and 2019-nCoV, with affinity binding between 600-800 RU (abstract, Supplementary Figure S1). Although Lei is silent on the equilibrium dissociation constant as being not greater than 50nM, this is a functional limitation inherent to the fusion protein as disclosed by the specification, which would necessarily be present in the fusion protein taught by combining the teachings of Battle and Lei.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the fusion proteins comprising ACE2 and IgG1 Fc domains as taught by Battle, and neutralize SARS-CoV-2 with said fusion proteins as taught by Lei with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to test these fusion proteins’ neutralization of the novel 2019 coronavirus, as recombinant ACE2 (rACE2) to protect against severe acute lung injury and acute Ang II-induced hypertension, conferring organ protection in both acute and chronic models of Ang-II dependent hypertension in mice, therefore, it would be obvious to evaluate the viral-binding affinity, the pharmaceutical effects, and therapeutic effects of ACE2 fusion proteins as claimed.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Battle and Yang as applied to claims 1, 3, 5, 8, 10, 14, 28, and 38 above, and further in view of Lei.
As discussed above, Battle teaches ACE2 is the cellular receptor for sudden acute respiratory syndrome (SARS) coronavirus/SARS-CoV and human coronavirus NL63/HCoV- NL63 [0043]. Yang teaches the formation of fusion protein complex wherein two fusion proteins are paired through a disulfide bond. Neither Battle nor Yang teach the protein complex is bound to a SARS-CoV-2 viral protein.
However, Lei teaches potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig (title). Lei teaches generation of a novel recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1, wherein the ACE2 mutant has low catalytic activity (abstract). Lei teaches both fusion proteins has high affinity binding to the RBD of SARS-CoV and 2019-nCoV, with affinity binding between 600-800 RU (abstract, Supplementary Figure S1, and Figure Legends of Figure 2 and Figure 3 on page 8).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a protein complex comprising the fusion protein complex as taught by Battle and Yang, and bind the SARS-CoV-2 viral protein as taught by Lei with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to utilize the fusion proteins taught by Battle and neutralize SARS-CoV-2 viral proteins as a therapeutic approach to neutralize the virus as taught by Lei.
Double Patenting
The nonstatutory double 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 nonstatutory double patenting 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 in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting 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 terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer 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 terminal disclaimer 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 may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5, 7-10, 17-18, 20, 28, and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, 8, 10-11, 13, 18, 20-23, 26-31 of copending Application No. 18/029043 in view of Lei.
Claims 1-2, 4-6, 8, 10-11, 13, 18, 20-23 of ‘043 recite a method of preventing, reducing a risk of, or treating a virus infection (COVID-19), comprising administering to a subject an effective amount of a fusion protein comprising ACE2 domain covalently attached to a Fc domain comprising a N-terminal or C-terminal deletion or both relative to a wild-type ACE2 having a SEQ ID NO: 1. Claim 2 of ‘043 recites the fusion protein comprises an amino acid having 98% sequence identity to SEQ ID NO: 15 which is 100% identical to instant SEQ ID NO: 15. Claims 26-31 of ‘043 also recite a liquid composition comprising said fusion protein. The instant claims do not explicitly recite the method of treating COVID-19 by administering the fusion protein recited in claims 1-2 of ‘043.
However, Lei teaches potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig (title). Lei teaches generation of a novel recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1, wherein the ACE2 mutant has low catalytic activity (abstract). Lei teaches both fusion proteins has high affinity binding to the receptor-binding domain (RBD) of SARS-CoV and 2019-nCoV and exerted desired pharmacological properties. Moreover, fusion proteins potently neutralized SARS-CoV and 2019-nCoV in vitro (abstract). Lei teaches DNA sequences of extracellular domains (ECDs) of ACE2 (aa: 1-740) were ligated to the Fc segment of human IgG1 and affinity tests were measured (pg. 5, Methods).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the fusion proteins comprising ACE2 and IgG1 Fc domain in the method of treating COVID19 recited in ‘043, to neutralize the SARS-CoV-2 virus as a therapeutic approach as taught by Lei with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to test these fusion proteins’ neutralization of the novel 2019 coronavirus, as recombinant ACE2 (rACE2) to protect against severe acute lung injury and acute Ang II-induced hypertension, conferring organ protection in both acute and chronic models of Ang-II dependent hypertension in mice, therefore, it would be obvious to evaluate the therapeutic potential of ACE2 fusion proteins and develop a method of treatment as claimed.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 5, 7-10, 14, 17-20, 28, and 38-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-6, 8, 10-11, 13, 18, 20-23, 26-31 of copending Application No. 18/029043 in view of Lei and Yang.
As discussed above, it would be prima facie obvious to utilize the recited fusion proteins in the instant claims and ‘043 in a method for treating COVID-19 as taught by Lei. ‘043 and Lei do not disclose the fusion proteins form a fusion protein complex, as recited in claims 14 and 19.
However, Yang teaches engineering Fc fragments with optimized physicochemical properties, and that Fc plays multiple roles in dimerization for formation of Y-shaped structure of Ig and maintenance of the structure, and Fc-mediated effector functions and extension of serum half-life; there are two domains: second constant domain (CH2) and third constant domain (CH3) in monomeric Fc of IgG, wherein two CH3 domains interact strongly with each other to form homodimer resulting in dimerization of Fc (title, pg. 2, col. 2, para 1). Yang teaches CH3 also contains seven β-strands from A to G connected by three loops (loops BC, DE, and FG) and two helices (helix 1 and 2) with a native disulfide bond between strand B (C367) and F (C425) as CH2 (Figure 1), and by distinguishing from two CH2 domain with in Fc, two CH3 domains can interact with each other very strongly, which leads to the formation of dimeric Fc structure, probably due to the homo-interaction, resulting in a dimeric CH3 that has much higher stability than monomeric CH2 (pg. 4, col, 2, para 2).
Therefore it would have been prima facie obvious to utilize the fusion proteins recited in the instant claims and ‘043 in a method of treating COVID-19 as taught by Lei, and further administer a fusion protein complex as taught by Yang with a reasonable expectation of success, because ACE2-Fc dimerizes through the hinge region of the Fc tag and that the Fc portion naturally exists as a dimer, resulting in a dimeric CH2 that has much higher stability than monomeric CH2.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657