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 .
Claim Status
Claims 1-11, 18-19, and 27-29 were previously pending. Applicant’s response of 04 December 2025 to the Non-Final Office Action was received. In that response, Applicant amended claims 1, 4, 18, and 27 and cancelled claims 3, and 8-11. Therefore, claims 1, 2, 4-7, 18-19, and 27-29 are currently pending and subject to examination.
Withdrawn Claim Rejections
Applicant has altered the scope of claim 1 wherein the erythropoietin (EPO) polypeptide of the fusion protein now requires a sequence identity of at least 90% with the corresponding sequence of wild-type (WT) EPO and has a C165R mutation. Therefore, all previous claim rejections are hereby withdrawn.
In view of Applicant cancelling claims 3 and 8-11, all previous rejections of these claims are moot and hereby withdrawn.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386 (c) was previously acknowledged and receipt of certified copies of papers required by 37 CFR 1.55 was previously acknowledged.
However, and as stated in the previous Office Action, the foreign priority document received on 09 December 2022 is not in English, and therefore, the examiner cannot ascertain whether said document discloses the invention for purposes of priority. Consequently, the effective filing date for applying prior art is 09 June 2021 (the date PCT/JP2021/021972 was filed).
New Claim Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 18-19 is new and not necessitated by amendment.
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.
Regarding instant claim 1, the erythropoietin amino acid sequence is not identified that requires “at least 90% identity with the corresponding sequence of wild-type erythropoietin” and further is not required to be a specific species. Additionally, while Felis catus EPO NCBI Accession NP_001009269 (https://www.ncbi.nlm.nih.gov/protein/NP_001009269.1) contains a C165 residue, other computationally determined EPO protein sequences of cats such as Prionailurus viverrinus EPO NCBI Accession XP_047693485 (https://www.ncbi.nlm.nih.gov/protein/XP_047693485.1) contain a S165 residue, not a C165. Therefore, the sequence of the wild-type erythropoietin polypeptide and 90% sequence identity erythropoietin polypeptides are indefinite. Thus, the metes and bounds of the claim are unclear. Claims 2, 5-7, 18-19, 27-29 are dependent on claim 1 without narrowing the claim to a specific erythropoietin polypeptide amino acid sequence and are also indefinite.
Claim 18 is rejected as being indefinite because claim 18 contains the following claim limitation in parenthesis: “…wherein the numbering of amino acids in the Fc region is based on EU Index of Kabat using Fc region of human antibody as the standard.” The content of the parentheses does not define or equate to the preceding terminology and thus is exemplary claim language which is unclear. Because this limitation is contained within a parenthesis, it is unclear if this limitation is a requirement of the claim or merely a suggestion. Because of this, one of ordinary skill could not determine the metes and bounds of the claim and therefore, claim 18 is indefinite. Claim 19 is dependent on claim 18 and includes the indefinite subject matter.
Claims 18 and 19 are rejected as being indefinite because both claims refer to substitution positions (e.g., “substitution of the 436-position histidine with threonine”) without any further guidance from the claims or disclosure. Table 1, pg. 18 ([0026]) of the specification discloses “[p]osition of dog, cat Fc alteration.” Specific variants are disclosed within Table 1; however, it remains unclear where exactly the substitutions occur. For instance, the right column indicates the substitution position is based on numbering wherein the start of cat Fc region SEQ ID NO: 2 is 1 but the left column indicates the substitutions occur “when human EU numbering is adapted to cat sequences.”
Looking to the examples, the Specification states that preferable alterations include: CFV-1: S434A, H436T, Q438R, and S440E ([0024], p. 16) wherein CFV-1 is represented by SEQ ID NO: 3 ([0027]). However, SEQ ID NO: 3 is only 219 amino acids in length, making positioning of these substitutions impossible.
Therefore, in claims 18 and 19, it is unclear whether the substitution position indicates the position within the Fc region where number 1 is the first amino acid of the entire fusion protein (EPO – hinge – Fc variant) or position 1 is the first amino acid of human IgG1 or something different. Further clarification is required.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 1-2, 4-7, 18-19, and 27-30 is new, but necessitated by amendment.
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 1-2, 4-7, 18-19, and 27-30 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.
Regarding claim 1, the erythropoietin polypeptide claimed is required to have a sequence identity of at least 90% with the corresponding sequence of wild-type erythropoietin and have a Cl65R mutation, but a sequence identity of 90% allows for changes to amino acids that are essential for erythropoietin polypeptide function. Claims 2, 5-7, 18-19, and 27-29 are dependent on claim 1 without narrowing the subject matter to an EPO sequence outside of the 90% sequence identity.
Scope of the claim
The claim is drawn to a fusion protein comprising an erythropoietin (EPO) polypeptide fused to the Fe region of a cat-derived IgG, wherein the erythropoietin polypeptide has sequence identity of at least 90% with the corresponding sequence of wild-type erythropoietin and has a Cl65R mutation, but the percent identity claimed only requires a C165R mutation and does not include other residues that allow EPO to function.
Examples in the specification
Applicant has disclosed two variants of the feline EPO-Fc with a single altered amino acid in the EPO region: O59P and C165R ([0082], Table 6). Therefore, with the required C165R mutation, Applicant has disclosed a variant that is 98.9% similar to WT feline EPO (both O59P and C165R) and another variant that is 99.5% similar to WT feline EPO (C165R). However, Applicant has not disclosed, with specificity, where variations up to 90% of erythropoietin may occur while still retaining the EPO function.
Prior art
The prior art taught erythropoietin (EPO) is a multifunctionality protein, depending on conditions, wherein the protein can act as a cytokine, a hormone, and a growth factor. (Uversky VN et al. Erythropoietin and co.: intrinsic structure and functional disorder. (Mol. BioSyst., 2017, 13,56-72) (page 56, left column, last paragraph). The prior art has shown while some amino acids have been shown to be required for EPO function, known functions of EPO are dependent on residues that are not fully delineated. Uversky taught glycosylation plays a fundamental role in the function of the various biological activities of EPO, affecting the solubility, cellular processing, secretion, and in vivo metabolism of this protein (page 56, right column, last paragraph). Uversky taught hEPO is glycosylated at three N-glycosylation sites, Asn24, Asn38, and Asn83, that are conserved in Chordata from fish to primates (page 57, left column, second paragraph). Functional properties of EPO of all amino acids are unclear though. Uversky taught EPO molecules have been created that entirely lack erythropoietic function, but show strong neuroprotection (page 57, left column, second paragraph). Additionally, changes to EPO can affect activities through more than one signaling pathway. Uversky taught induction of non-erythropoietic functions of EPO is related to the interaction with the heterodimeric EpoR/βCR receptor, which requires high local concentrations of EPO. Uversky taught this is in a contrast to the initiation of the erythropoietic functions of EPO, which relies on the binding of picomolar concentrations of this cytokine to the canonical (EpoR)2 homodimers.
Thus, exchanging amino acids of EPO to 90% can cause functional changes to the EPO protein that affect function to multiple pathways in unpredictable ways. Thus, Applicant was not in possession of a fusion protein comprising an erythropoietin polypeptide fused to the Fc region of a cat-derived IgG, wherein the erythropoietin polypeptide has sequence identity of at least 90% with the corresponding sequence of wild-type erythropoietin and has a Cl65R mutation in claims 1-2, 5-7, 18-19, and 27-29.
Claim Rejections - 35 USC § 103
The rejection of claims 1-2, 4-7, 18-19, and 27-30 is new, but necessitated by amendment.
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.
Claims 1, 4, 7, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (previously cited in prior office action as: US 10,287,336 B2; date of patent: 14 May 2019) in view of Zhan (previously cited in prior office action as: US 2022/0025005 A1; published: 27 January 2022), Shi X et al. (PLoS ONE 2013 8(8):e72673 1-7), and UniProt (P01588 EPO_HUMAN, amino acid sequence last updated: 21 July 1986).
As a reminder: The subject matter disclosed by Zhan, as it pertains to the rejected claims, was first disclosed in either 62/785,691 (filed on 12 December 2018) with which US 2022/0025005 A1 claims priority or PCT/US2019/66052 (filed on 12 December 2019) with which US 2022/0025005 A1 is a 371 national stage application – both of which are before the effective filing date of the instant application by more than 1 year.
Regarding instant claim 1, Lu discloses peptide EPOR agonists fused to feline IgG Fc to form fusion proteins consisting of a feline EPO and a linker fused to the N- or C-terminus of an Fc fragment that may be obtained from a cat (Fig. 2A and Fig. 2B; col. 3, lines 19-35; col. 14, lines 1-2). Lu further describes the EPO may be a variant of a wild-type which increases the half-life therefore increasing the in vivo duration of efficacy and titer when compared to the native EPO (col. 29, lines 56-67). Regarding instant claims 1-2, Lu taught an EPO agonist comprising GGTYSCHFGPLTBVCRPQGG and feline IgG1a Fc fusion protein was expressed, harvested, and found as effective in a cell-based activity assay (Fig. 5). Regarding instant claim 2, Lu taught SEQ ID NO:2 as the feline IgG Fc, wherein SEQ ID NO:2 begins with the hinge region (col. 1, paragraph 3). Regarding instant claim 7, Lu taught the Fc region has modifications to further extend the in vivo half-life of the antibody molecule or Fc fusion protein (col. 14, lines 55-66) that include amino acid mutations (col. 16, lines 7-11). Regarding instant claim 28, Lu discloses the fusion protein in a pharmaceutical composition (col. 22, lines 54-57). Regarding instant claim 29, Lu discloses the fusion protein in the pharmaceutical composition is administered to a subject suspected of anemia thereby treating the subject effectively (col. 22, lines 33-39). Lu taught EPO regulates erythropoiesis (red blood cell production) (col. 1, lines 28-30).
Lu does not explicitly describe an EPO-Fc fusion with a C165R mutation, but this is obvious in view of Zhan, Shi, and Uniprot.
Zhan taught there is an unmet need, for methods and compounds that can be used to treat anemia in cats, wherein ideally, the compounds would bind specifically to EPO receptor and have a half-life in plasma sufficiently long to be practicable for therapy (page 1, [0006]). Zhan taught treatment of felines with a pharmaceutical composition comprising an EPO polypeptide to treat EPO deficient or EPO insensitivity-induced conditions (page 39, [0521]). Regarding instant claim 1, Zhan taught a feline EPO variant with mutant C165X of ‘005 SEQ ID NO:122, wherein X may be any amino acid (page 28, Table 1). Zhan taught an unpaired cysteine may cause undesirable effects, such as disulfide scrambling (incorrect disulfide bond formation) and intermolecular covalent disulfide binding and that cysteine 165 is an unpaired cysteine that may be replaced with any other amino acid (page 49, [0625]).
Regarding instant claim 4, Zhan taught the EPO analog ‘005 SEQ ID NO: 122, which shares 99.4% similarity to SEQ ID NO: 10 of the instant application (when not taking into account the wildcard X at position 165 of SEQ ID NO: 122):
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Zhan further discloses the X wildcard in EPO polypeptide represented by SEQ ID NO: 122 can be any amino acid other than a cysteine ([0438]). Therefore, within the limitations disclosed by Zhan, SEQ ID NO: 122 shares 100% sequence identity to instant SEQ ID NO: 10 by substituting arginine for X wildcard. While Zhan describes a C165X mutation of feline EPO that is advantageous, Zhan only discloses X can be any amino acid and does not explicitly disclose a C165R mutation.
Shi taught rhEPO-Fc compositions are effective in vivo (abstract). Thus, EPO-Fc fusions of full length EPO are effective.
UniProt discloses the human wild-type EPO sequence. When aligned to the wild-type feline EPO sequence, the human EPO sequence contains arginine at the position where the feline EPO sequence contains a cysteine as shown below:
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Regarding instant claims 1, 4, 7, and 28-29, it would have been obvious for a person having ordinary skill in the art to take the effective pharmaceutical composition of an EPO agonist comprising EPO GGTYSCHFGPLTBVCRPQGG and IgG1a Fc fusion protein of Lu – and:
include Lu SEQ ID NO:2 as the IgG Fc, which begins with a hinge region as taught by Lu;
include an Fc region modification to further extend the in vivo half-life of the Fc fusion protein as taught by Lu;
administer the composition to a subject to treat anemia which is a hematopoietic disease;
exchange the EPO agonist of Lu attached to the IgG Fc with a feline EPO variant with mutant C165X of Zhan SEQ ID NO:122, wherein X may be any amino acid in view of Zhan;
Exchange the C165X mutation with C165R in view of Zhan and Uniprot;
This is obvious because:
Lu taught SEQ ID NO:2 as the feline IgG Fc;
Lu taught the Fc region has modifications to further extend the in vivo half-life of the Fc fusion protein;
Lu taught the fusion protein in the pharmaceutical composition is administered to a subject suspected of anemia thereby treating the subject effectively;
4a) Lu taught the EPO may be a variant of a wild-type which increases the half-life therefore increasing the in vivo duration of efficacy and titer when compared to the native EPO;
4b) Zhan taught a feline EPO variant with mutant C165X of Zhan SEQ ID NO:122, wherein X may be any amino acid;
4c) Zhan taught an unpaired cysteine may cause undesirable effects, such as disulfide scrambling (incorrect disulfide bond formation) and intermolecular covalent disulfide binding and that cysteine 165 is an unpaired cysteine that may be replaced with any other amino acid;
4d) Shi taught rhEPO-Fc compositions are effective in vivo. Thus, EPO-Fc fusions of full length EPO are effective;
5) Zhan taught C165 as any amino acid and other species with EPO such as human EPO has an arginine at the 165 position and is effective.
There is a reasonable expectation of success because:
EPO agonist-IgG Fc constructs are known to be effective;
Fc region modifications can further extend the in vivo half-life of the Fc fusion protein;
EPO regulates erythropoiesis (red blood cell production) and would increase red blood cell production;
4a) EPO agonist-IgG Fc constructs are known to be effective;
4b) Zhan taught an unpaired cysteine may cause undesirable effects, such as disulfide scrambling (incorrect disulfide bond formation) and intermolecular covalent disulfide binding and that cysteine 165 is an unpaired cysteine that may be replaced with any other amino acid;
4c) Shi taught rhEPO-Fc compositions are effective in vivo. Thus, EPO-Fc fusions of full length EPO are effective;
5) human EPO has an arginine at the 165 position, is effective, and arginine would prevent disulfide scrambling and intermolecular covalent disulfide binding.
This would produce a method of treating anemia, which is a hematopoietic disease, of administering to a subject in need thereof (instant claim 29) a pharmaceutical composition (instant claim 28) comprising an EPO fusion of Zhan SEQ ID NO:122 with a C165R mutation and feline IgG1 Fc Zhan SEQ ID NO:2 which begins with the IgG hinge region, wherein the EPO polypeptide sequence is identical to instant SEQ ID NO:10 (claim 4) and the IgG1 Fc comprises an Fc region modification (instant claim 7) (instant claim 1).
The fusion protein sequence would be:
MGSCECPALLLLLSLLLLPLGLPVLGAPPRLICDSRVLERYILEAREAENVTMGCAEGCSFSENITVPDTKVNFYTWKRMDVGQQAVEVWQGLALLSEAILRGQALLANSSQPSETLQLHVDKAVSSLRSLTSLLRALGAQKEATSLPEATSAAPLRTFTVDTLRKLFRIYSNFLRGKLTLYTGEACRRGDR
-feline IgG1 Fc of Zhan SEQ ID NO:2 which begins with a hinge region
RKTDHPPGPKPCDCPKCPPPEMLGGPSIFIFPPKPKDTLSISRTPEVTCLVVDLGPDDSDVQITWFVDNTQVYTAKTSPREEQFNSTYRVVSVLPILHQDWLKGKEFKCKVNSKSLPSPIERTISKAKGQPHEPQVYVLPPAQEELSRNKVSVTCLIKSFHPPDIAVEWEITGQPEPENNYRTTPPQLDSDGTYFVYSKLSVDRSHWQRGNTYTCSVSHEALHSHHTQKSLTQSPGK, wherien the further Fc region modification is not shown.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Applicant argues a person of ordinary skill in the art would not have had a reasonable expectation of success in modifying the EPO-Fc fusion protein disclosed by Lu et al. to include any of the representative feline EPO polypeptides disclosed by Zhan et al., let alone to arrive at the present invention as defined by claim 1 or, therefore, prior claim 4 dependent thereon.
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As is apparent from the foregoing summary, the only Examples in Zhan et al. that
provide insights into variants of feline EPO are Examples 17 and 18, and, among them, Example 18 is the only one that focuses on the mutation of Cl39 (or Cl65 in the precursor
form).
A person of ordinary skill in the art could identify potential substitution sites for
glycosylation (Example 17) and for cysteine residues for structural stabilization (Example 18), as exemplified in the respective Examples. However, even a single amino acid mutation can significantly alter the physicochemical and biological properties of a protein, and such effects were difficult to predict for variants of feline EPO at the time of Zhan et al.
Moreover, in Example 18 of Zhan et al., the possibility of substituting C139
(corresponding to Cl65 in the present invention) is mentioned only with respect to threonine, serine, and alanine, albeit as optional examples. These amino acids share similar chemical
properties with cysteine (such as size, polarity, and nucleophilicity), and such substitutions
can be regarded as conservative substitutions. In contrast, the feline EPO variant used in the
present invention includes a Cl65R substitution, and the replacement of cysteine with
arginine at C 165 cannot be considered a conservative substitution.
A person of ordinary skill in the art would have understood that whether a variant is
beneficial or not must actually be verified by creating the variant and experimentally testing
its effect. However, even from the perspective of the common general knowledge in the art,
while conservative substitutions might conceivably be predictable, a non-conservative
substitution such as cystine to arginine cannot be expected to have a predictable effect
without experimental verification.
Accordingly, the present invention as defined by the pending claims - which require a
mutated erythropoietin polypeptide, specifically with at least a Cl65R mutation, would not
have been obvious based on Lu et al. and Zhan et al., such that the obviousness rejection
based on Lu et al. and Zhan et al. should be withdrawn.
In response, Applicant's arguments filed 12/4/2025 have been fully considered but they are not persuasive. Lu taught an EPO agonist comprising GGTYSCHFGPLTBVCRPQGG and feline IgG1a Fc fusion protein was expressed, harvested, and found as effective in a cell-based activity assay (Fig. 5). Thus, EPO-Fc feline fusions are known to be effective. Shi taught rhEPO-Fc compositions are effective in vivo. Thus, EPO-Fc fusions of full length EPO are effective. Zhan taught a feline EPO variant with mutant C165X of Zhan SEQ ID NO:122, wherein X may be any amino acid. Zhan taught an unpaired cysteine may cause undesirable effects, such as disulfide scrambling (incorrect disulfide bond formation) and intermolecular covalent disulfide binding and that cysteine 165 is an unpaired cysteine that may be replaced with any other amino acid. Thus, EPO cysteine 165 would be expected to have negative effects and exchange would be preferred. Regarding exchange of the C165 to R, Zhan taught C165 as any amino acid and human EPO-Fc fusion constructs are known to be effective as taught by Shi. Thus, exchange of the C165 to R which is present in human EPO would be obvious with a reasonable expectation of success.
In response to even a single amino acid mutation can significantly alter the physicochemical and biological properties of a protein and Zhan suggests substituting to T, S, and A – there are mechanistic reasons for exchange of the cysteine 165 as taught by Zhan above. Further, the effective human EPO-Fc of Shi and wild-type human EPO taught by Uniprot would suggest to a person having ordinary skill in the art that it would be obvious with a reasonable expectation of success to exchange the C165 to R without negatively affecting physicochemical and biological properties. The exchange would be expected to positively affecting physicochemical and biological properties of the fusion protein.
Claims 1-2, 4-7, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (previously cited in prior office action as: US 10,287,336 B2; date of patent: 14 May 2019), Zhan (previously cited in prior office action as: US 2022/0025005 A1; published: 27 January 2022), Shi X et al. (PLoS ONE 2013 8(8):e72673 1-7), UniProt (P01588 EPO_HUMAN, amino acid sequence last updated: 21 July 1986) as applied to claims 1, 4, 7, and 28-29 above, and further in view of Wang (previously cited in prior office action as: US 2019/0070307 A1; published: 07 March 2019)
The teachings of Lu, Zhan, Shi, and UniProt are discussed above.
Lu did not teach: 1) direct linkage of EPO to the IgG Fc without a linker or 2) an IgG hinge region with a cysteine to glycine mutation, but this is obvious in view of Wang.
Wang discloses recombinant human EPO-Fc fusion proteins with prolonged half-life and enhanced EPO activity in vivo (title). Regarding instant claim 2, Wang taught the EPO molecule is linked directly to the Fc fragment to avoid extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo (abstract). Wang taught the EPO-Fc fusion was effective in vivo (Fig 6A-B). Wang discloses the EPO peptide is linked directly to the hinge region ([0015]) which gives the same general shape as an IgG molecule and exhibit increased stability compared to free EPO molecules ([0016]). Wang further discloses the hinge region in the rHuEPO-Fc fusion protein maintains flexibility, especially when the fusion protein is in the dimer form to allow fusion EPO binding to EPO receptors to activate EPO biological functions ([0036]).
Regarding instant claims 5-6, Wang taught substitution of the first cysteine residue within the Fc hinge portion to a glycine as a non-cysteine residue, wherein the first cysteine residue is not involved in Fc hinge disulfide bonding ([0020 and 0039-0040]). Wang taught if the first cysteine residue of the hinge was not mutated it could form an undesirable disulfide bond with EPO, which may alter the three dimensional structure of the EPO molecule, resulting in biological inactivity or reduced biological activity ([0040]).
Regarding instant claims 2 and 5-6, it would have been obvious for a person having ordinary skill in the art to take the method of Lu, Zhan, and Uniprot above of a method of treating anemia by of administering to a subject in need thereof a pharmaceutical composition comprising an EPO-Fc fusion of Zhan SEQ ID NO:122 with a C165R mutation and feline IgG1 Fc Zhan SEQ ID NO:2 which begins with the IgG hinge region and further comprises an Fc region modification – and:
Fuse the EPO directly to the Fc IgG1 in view of Wang;
Substitute the first cysteine in the feline IgG1 Fc Zhan SEQ ID NO:2 for glycine in view of Wang;
This is obvious because:
Wang taught the EPO-Fc fusion was effective in vivo and that direct linkage to the Fc fragment avoids extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo;
2a) Wang taught substitution of the first cysteine residue within the Fc hinge portion to a glycine as a non-cysteine residue, wherein the first cysteine residue is not involved in Fc hinge disulfide bonding
2b) Wang taught if the first cysteine residue of the hinge was not mutated it could form an undesirable disulfide bond with EPO, which may alter the three dimensional structure of the EPO molecule, resulting in biological inactivity or reduced biological activity;
There is a reasonable expectation of success because:
Direct EPO-Fc fusion was effective in vivo and avoids extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo;
2a) Wang taught the first cysteine residue of the hinge IgG Fc is not involved in Fc hinge disulfide bonding;
2b) Wang taught if the first cysteine residue of the hinge was not mutated to glycine the fusion protein could form an undesirable disulfide bond with EPO, which may alter the three dimensional structure of the EPO molecule, resulting in biological inactivity or reduced biological activity;
This would produce a method of a method of treating anemia by of administering to a subject in need thereof a pharmaceutical composition comprising an EPO-Fc fusion of Zhan SEQ ID NO:122 with a C165R mutation directly fused (instant claim 2) to feline IgG1 Fc Zhan SEQ ID NO:2 which begins with the IgG hinge region wherein the first cysteine of the hinge region is substituted with glycine, which would be identical to instant SEQ ID NO:5 (instant claims 5-6), and further comprises an Fc region modification
The EPO- feline IgG1 Fc fusion protein sequence would be:
EPO sequence-
MGSCECPALLLLLSLLLLPLGLPVLGAPPRLICDSRVLERYILEAREAENVTMGCAEGCSFSENITVPDTKVNFYTWKRMDVGQQAVEVWQGLALLSEAILRGQALLANSSQPSETLQLHVDKAVSSLRSLTSLLRALGAQKEATSLPEATSAAPLRTFTVDTLRKLFRIYSNFLRGKLTLYTGEACRRGDR
Hinge sequnce-
RKTDHPPGPKPGDCPKCP-
Fc sequence-PPEMLGGPSIFIFPPKPKDTLSISRTPEVTCLVVDLGPDDSDVQITWFVDNTQVYTAKTSPREEQFNSTYRVVSVLPILHQDWLKGKEFKCKVNSKSLPSPIERTISKAKGQPHEPQVYVLPPAQEELSRNKVSVTCLIKSFHPPDIAVEWEITGQPEPENNYRTTPPQLDSDGTYFVYSKLSVDRSHWQRGNTYTCSVSHEALHSHHTQKSLTQSPGK, wherien the further Fc region modification is not shown.
Claims 1-2, 4-7, 18-19, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (previously cited), Zhan (previously cited), Shi X et al. (PLoS ONE 2013 8(8):e72673 1-7), UniProt (previously cited), and Wang (previously cited in prior office action as: US 2019/0070307 A1; published: 07 March 2019) as applied to claims 1-2, 4-7, and 28-29 above, and further in view of Brondyk (US 11,498,953 B2; date of patent: 15 November 2022; priority date: 10 July 2020) and US 2014/0363428 (Igawa et al.)
Of Note: the subject matter disclosed by Brondyk, as it pertains to the rejected claims, was first disclosed in 63/050,535 (filed on 10 July 2020) with which US Patent 11,498,953 B2 claims priority.
The teachings of Lu, Zhan, Shi, UniProt, and Wang are discussed above.
Lu did not teach: 1) Fc substitutions of S428L, S434A, Q438R, and S440E, but this is obvious in view of Brondyk and Igawa.
Brondyk discloses feline IgG variants for increasing the half-life of a polypeptide(s) in a feline and methods of their use (abstract). Regarding instant claims 18-19 and 27, Brondyk taught substitutions for increased FcRN binding at the following positions corresponding to the wild-type feline IgG: S428L (col. 20, lines 9-13); and S434F or S434Y (col. 20, lines 19-23); and S434A (col. 22, Table 2). Brondyk identifies these substitutions alone or in combination are responsible for increased half-life (see col. 19, 20, 21, and 22).
Igawa taught an antigen-binding molecule having an increased binding activity for the FcRn and a binding affinity for a pre-existing anti-drug antibody that is not significantly increased as compared to a Control Antigen-binding Molecule, comprising amino acid substitutions at 438R/440E (page 22, [0249]), wherein Fc Q438R/S440E mutations effectively reduced rheumatoid factor binding (page 75, [0555-0556], Table 25, and Fig. 32).
Regarding instant claims 18-19 and 27, it would have been obvious for a person having ordinary skill in the art to take the EPO- feline IgG1 Fc fusion protein of Lu, Zhan, UniProt, and Wang above – and: 1) include the Fc substitutions of S428L, S434A in view of Brondyk; and 2) Q438R, and S440E in view of Igawa.
This is obvious because: 1) Brondyk taught substitutions in the wild-type feline IgG of S428L and S434A increase FcRN binding to increase half-life; and 2) Igawa taught an antigen-binding molecule having an increased binding activity for the FcRn and a binding affinity for a pre-existing anti-drug antibody that is not significantly increased as compared to a Control Antigen-binding Molecule, comprising amino acid substitutions at 438R/440E, wherein Fc Q438R/S440E mutations effectively reduced rheumatoid factor binding.
There is a reasonable expectation of success because: 1) Brondyk taught substitutions in the wild-type feline IgG of S428L and S434A increase FcRN binding to increase half-life; and 2) Igawa taught an antigen-binding molecule having an increased binding activity for the FcRn and a binding affinity for a pre-existing anti-drug antibody that is not significantly increased as compared to a Control Antigen-binding Molecule, comprising amino acid substitutions at 438R/440E, wherein Fc Q438R/S440E mutations effectively reduced rheumatoid factor binding.
This would produce a sequence of the EPO-Fc fusion as
EPO
MGSCECPALLLLLSLLLLPLGLPVLGAPPRLICDSRVLERYILEAREAENVTMGCAEGCSFSENITVPDTKVNFYTWKRMDVGQQAVEVWQGLALLSEAILRGQALLANSSQPSETLQLHVDKAVSSLRSLTSLLRALGAQKEATSLPEATSAAPLRTFTVDTLRKLFRIYSNFLRGKLTLYTGEACRRGDR
-IgG Fc fusion
RKTDHPPGPKPGDCPKCPPPEMLGGPSIFIFPPKPKDTLSISRTPEVTCLVVDLGPDDSDVQITWFVDNTQVYTAKTSPREEQFNSTYRVVSVLPILHQDWLKGKEFKCKVNSKSLPSPIERTISKAKGQPHEPQVYVLPPAQEELSRNKVSVTCLIKSFHPPDIAVEWEITGQPEPENNYRTTPPQLDSDGTYFVYSKLSVDRSHWQRGNTYTCSVLHEALHAHHTRKELTQSPGK
Wherein the sequence is identical to instant SEQ ID NO:3 (instant claim 27) and comprises Fc substitutions of S428L, S434A, Q438R, and S440E (instant claims 18-19).
Double Patenting
The following rejection is necessitated by amendment to the claims.
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).
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US 12,351,622 (date of patent: 08 July 2025)
Claims 1, 4, 7, 18-19, and 27-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 12,351,622 (hereinafter ‘622) in view of Lu (previously cited), Zhan (previously cited), Shi X et al. (PLoS ONE 2013 8(8):e72673 1-7), and UniProt (previously cited).
Regarding instant claims 1, 4, 7, 18-19, and 27-29, patent ‘622 claims a parent polypeptide with an Fc region of a cat IgG that shows a higher binding activity to a cat neonatal Fc receptor (FcRn), wherein the Fc region has modifications of substitutions of i) S428L; ii) S434A; iii) Q438R; and iv) S440E in patented claim 1, and wherein the Fc region is an Fc fusion in patented claim 2.
The claims of ‘622 did not teach: 1) an EPO fusion-Fc wherein a C165R mutation is present in the EPO sequence; 2) a pharmaceutical composition; or 3) a treatment of a hematopoiesis disease, but this is obvious in view of Lu, Zhan, and Uniprot.
The teachings of Lu, Zhan, Shi, and UniProt, are discussed above.
Regarding instant claim 1, 4, 7, 18-19, and 27-29, it would have been obvious for a person having ordinary skill in the art to take the patented claims 1-2 of a fusion-Fc protein of a cat IgG, that shows a higher binding activity to a cat neonatal Fc receptor FcRn with substitutions of i) S428L; ii) S434A; iii) Q438R; and iv) S440E – and:
Attach an EPO agonist to the modified Fc domain of a feline EPO variant with mutant C165X of Zhan SEQ ID NO:122, wherein X may be any amino acid in view of Lu and Zhan;
Exchange the C165X mutation with C165R in view of Zhan and Uniprot;
Include the EPO-IgG Fc modified fusion protein in a pharmaceutical composition; and
administer the composition to a subject to treat anemia which is a hematopoietic disease.
This is obvious because:
1a) Lu taught a pharmaceutical composition of a feline EPO agonist-IgG Fc is effective;
1b) Lu taught the EPO may be a variant of a wild-type which increases the half-life therefore increasing the in vivo duration of efficacy and titer when compared to the native EPO;
1c) Zhan taught a feline EPO variant with mutant C165X of Zhan SEQ ID NO:122, wherein X may be any amino acid;
1d) Zhan taught an unpaired cysteine may cause undesirable effects, such as disulfide scrambling (incorrect disulfide bond formation) and intermolecular covalent disulfide binding and that cysteine 165 is an unpaired cysteine that may be replaced with any other amino acid;
1e) Shi taught rhEPO-Fc compositions are effective in vivo. Thus, EPO-Fc fusions of full length EPO are effective;
Zhan taught C165 as any amino acid and other species with EPO such as human EPO has an arginine at the 165 position and is effective;
Lu taught a pharmaceutical composition of a feline EPO agonist-IgG Fc is effective; and
Lu taught the fusion protein in the pharmaceutical composition is administered to a subject suspected of anemia thereby treating the subject effectively.
There is a reasonable expectation of success because:
1a) EPO agonist-IgG Fc constructs are known to be effective;
1b) Fc region modifications can further extend the in vivo half-life of the Fc fusion protein;
1c) Zhan taught an unpaired cysteine may cause undesirable effects, such as disulfide scrambling (incorrect disulfide bond formation) and intermolecular covalent disulfide binding and that cysteine 165 is an unpaired cysteine that may be replaced with any other amino acid;
1d) Shi taught rhEPO-Fc compositions are effective in vivo. Thus, EPO-Fc fusions of full length EPO are effective;
human EPO has an arginine at the 165 position, is effective, and arginine would prevent disulfide scrambling and intermolecular covalent disulfide binding;
Lu taught a pharmaceutical composition of a feline EPO agonist-IgG Fc is effective; and
EPO regulates erythropoiesis (red blood cell production) and would increase red blood cell production.
This would produce a method of treating anemia, which is a hematopoietic disease, of administering to a subject in need thereof (instant claim 29) a pharmaceutical composition (instant claim 28) comprising an EPO fusion of Zhan SEQ ID NO:122 with a C165R mutation and feline IgG1 Fc Zhan SEQ ID NO:2 which begins with the IgG hinge region, and further comprises i) S428L; ii) S434A; iii) Q438R; and iv) S440E substitutions wherein the sequence is identical to instant SEQ ID NO:3 (instant claim 27) and comprises Fc substitutions of S428L, S434A, Q438R, and S440E (instant claims 7 and 18-19), and wherein the EPO polypeptide sequence is identical to instant SEQ ID NO:10 (claim 4) (instant claim 1).
The fusion protein sequence would be:
MGSCECPALLLLLSLLLLPLGLPVLGAPPRLICDSRVLERYILEAREAENVTMGCAEGCSFSENITVPDTKVNFYTWKRMDVGQQAVEVWQGLALLSEAILRGQALLANSSQPSETLQLHVDKAVSSLRSLTSLLRALGAQKEATSLPEATSAAPLRTFTVDTLRKLFRIYSNFLRGKLTLYTGEACRRGDR
-feline IgG1 Fc of Zhan SEQ ID NO:2 and further comprises i) S428L; ii) S434A; iii) Q438R; and iv) S440E substitutions which begins with a hinge region
RKTDHPPGPKPCDCPKCPPPEMLGGPSIFIFPPKPKDTLSISRTPEVTCLVVDLGPDDSDVQITWFVDNTQVYTAKTSPREEQFNSTYRVVSVLPILHQDWLKGKEFKCKVNSKSLPSPIERTISKAKGQPHEPQVYVLPPAQEELSRNKVSVTCLIKSFHPPDIAVEWEITGQPEPENNYRTTPPQLDSDGTYFVYSKLSVDRSHWQRGNTYTCSVLHEALHAHHTRKELTQSPGK
and comprises Fc substitutions of S428L, S434A, Q438R, and S440E.
Claims 1-2, 4-7, 18-19, and 27-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 12,351,622 (hereinafter ‘622) in view of Lu (previously cited), Zhan (previously cited), Shi X et al. (PLoS ONE 2013 8(8):e72673 1-7), UniProt (previously cited) and Wang (previously cited in prior office action as: US 2019/0070307 A1; published: 07 March 2019).
The claims of the ‘622 patent in view of Lu, Zhan, and Uniport teach the limitations of claims 1, 4, 7, 18-19, and 27-29 for the reasons set forth above.
The teachings of ‘622, Lu, Zhan, Shi, and UniProt are discussed above.
‘622 is silent to: 1) direct linkage of EPO to the IgG Fc without a linker or 2) an IgG hinge region with a cysteine to glycine mutation, but this is obvious in view of Wang.
Wang is described above.
Regarding instant claims 2 and 5-6, it would have been obvious for a person having ordinary skill in the art to take the method of ‘622, Lu, Zhan, Shi, and Uniprot above – and modify the EPO fusion of Zhan SEQ ID NO:122 with a C165R mutation and feline IgG1 Fc Zhan SEQ ID NO:2 which begins with the IgG hinge region, and further comprises i) S428L; ii) S434A; iii) Q438R; and iv) S440E substitution to:
Fuse the EPO directly to the Fc IgG1 in view of Wang;
Substitute the first cysteine in the feline IgG1 Fc Zhan SEQ ID NO:2 for glycine in view of Wang;
This is obvious because:
Wang taught the EPO-Fc fusion was effective in vivo and that direct linkage to the Fc fragment avoids extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo;
2a) Wang taught substitution of the first cysteine residue within the Fc hinge portion to a glycine as a non-cysteine residue, wherein the first cysteine residue is not involved in Fc hinge disulfide bonding
2b) Wang taught if the first cysteine residue of the hinge was not mutated it could form an undesirable disulfide bond with EPO, which may alter the three dimensional structure of the EPO molecule, resulting in biological inactivity or reduced biological activity;
There is a reasonable expectation of success because:
Direct EPO-Fc fusion was effective in vivo and avoids extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo;
2a) Wang taught the first cysteine residue of the hinge IgG Fc is not involved in Fc hinge disulfide bonding;
2b) Wang taught if the first cysteine residue of the hinge was not mutated to glycine the fusion protein could form an undesirable disulfide bond with EPO, which may alter the three dimensional structure of the EPO molecule, resulting in biological inactivity or reduced biological activity;
This would produce a method of a method of treating anemia by of administering to a subject in need thereof a pharmaceutical composition comprising an EPO-Fc fusion of Zhan SEQ ID NO:122 with a C165R mutation directly fused (instant claim 2) to feline IgG1 Fc Zhan SEQ ID NO:2 and further comprises i) S428L; ii) S434A; iii) Q438R; and iv) S440E substitutions which begins with the IgG hinge region wherein the first cysteine of the hinge region is substituted with glycine, which would be identical to instant SEQ ID NO:5 (instant claims 5-6),
The fusion protein sequence would be:
MGSCECPALLLLLSLLLLPLGLPVLGAPPRLICDSRVLERYILEAREAENVTMGCAEGCSFSENITVPDTKVNFYTWKRMDVGQQAVEVWQGLALLSEAILRGQALLANSSQPSETLQLHVDKAVSSLRSLTSLLRALGAQKEATSLPEATSAAPLRTFTVDTLRKLFRIYSNFLRGKLTLYTGEACRRGDR
-feline IgG1 Fc of Zhan SEQ ID NO:2 and further comprises i) S428L; ii) S434A; iii) Q438R; and iv) S440E substitutions which begins with a hinge region
RKTDHPPGPKPGDCPKCPPPEMLGGPSIFIFPPKPKDTLSISRTPEVTCLVVDLGPDDSDVQITWFVDNTQVYTAKTSPREEQFNSTYRVVSVLPILHQDWLKGKEFKCKVNSKSLPSPIERTISKAKGQPHEPQVYVLPPAQEELSRNKVSVTCLIKSFHPPDIAVEWEITGQPEPENNYRTTPPQLDSDGTYFVYSKLSVDRSHWQRGNTYTCSVLHEALHAHHTRKELTQSPGK
and comprises Fc substitutions of S428L, S434A, Q438R, and S440E.
Response to Arguments
Independent claim 1 has been amended.
The updated rejection is above.
Conclusion
Claims 1-2, 4-7, 18-19, and 27-29 are rejected.
Conclusion
Claims 1-2, 4-7, 18-19, and 27-29 are rejected. No claim is allowed.
Communication
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/JULIA A ROSSI/Examiner, Art Unit 1644
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643