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 1-2, 4-7, 18-19, and 27-29 were previously pending.
A non-final rejection office action was mailed 09 March 2026.
In response to that office action, Applicant filed an amendment/request for reconsideration received 09 June 2026.
In their response, Applicant amended claims 1, 6, and 18 and cancelled claims 2 and 5.
Therefore, claims 1, 4, 6-7, 18-19, and 27-29 are now pending and currently under examination.
Withdrawn Claim Rejections
I. The previous 35 USC 112(b) rejection of claim 1, and claims 2, 5-7, 18-19, and 27-29 for depending on and failing to cure the defect of claim 1, regarding the erythropoietin amino acid sequence is hereby withdrawn. Applicant has amended claim 1 to include wild-type erythropoietin of SEQ ID NO: 11.
II. The previous 35 USC 112(b) rejection of claim 18, and claim 19 for depending on and failing to cure the defect of claim 18, regarding the limitation in parenthesis is hereby withdrawn. Applicant has amended claim 18 to remove the parenthesis.
III. The previous 35 USC 103 rejection of claims 1, 4, 7, and 28-29 as being unpatentable over Lu, Zhan, Shi X, and UniProt is hereby withdrawn. Applicant has incorporated the limitations of now cancelled claims 2 and 5 into independent claim 1, thus changing the scope of the claim.
Maintained Claim Rejections
The following rejections are maintained and have only been amended to incorporate Applicant’s claim amendments.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 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.
Response to Applicant’s Arguments
Applicant’s arguments have been considered, but are not persuasive. Applicant argues the residue positions recited in claims 18 and 19 correspond to positions assigned according to a modified EU numbering system using a human Fc region as a reference. However, claim 18 depends from claim 1, which broadly recites an Fc region of “cat-derived IgG” and does not limit the Fc region to a particular amino acid sequence. Thus, it is unclear from the claim language whether, for example, “the 434-position serine” refers to a residue corresponding to human EU position 434 following sequence alignment with any Fc region of cat-derived IgG or a position defined with reference to one of the particular feline Fc sequences disclosed in the specification (e.g., CFV-1, CFV-2, etc. as recited in Table 1, p. 18). Applicant’s reliance on Table 1 does not resolve this ambiguity because the claim is not limited to the particular Fc sequence represented in Table 1 (SEQ ID NO: 2). Accordingly, the metes and bounds of claims 18 and 19 remain unclear.
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.
Claims 1, 4, 6-7, 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, 6-7, 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, 6-7, 18-19, and 27-29.
Response to Applicant’s Arguments
Applicant’s arguments have been considered, but are not persuasive. Applicant argues the amendment of claim 1 to require the erythropoietin polypeptide “has an activity that stimulates the proliferation and development of erythrocytes from erythrocyte progenitor cells” overcomes the written description rejection under 35 USC 112(a). The argument is not persuasive because the newly added functional limitation does not cure the lack of adequate descriptive support for the full structural breadth of the claimed genus.
Claim 1 encompasses erythropoietin polypeptides having as little as 90% sequence identity to the wild-type feline erythropoietin sequence of SEQ ID NO: 11, provided the polypeptide contains the recited C165R mutation and retains the newly claimed erythropoietic activity. Thus, the claim encompasses numerous sequence variants differing substantially from the particular erythropoietin sequence exemplified in the specification.
As previously explained, the specification describes only a limited number of erythropoietin species within the claimed genus, including 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. The specification does not disclose a representative number of species spanning the full scope of sequences having at least 90% identity, nor does it identity structural characteristics or provide a structure-function correlation sufficient to permit one of ordinary skill in the art to recognize which of the numerous additional amino acid substitutions encompassed by the claim would retain the recited erythropoietic activity.
The addition of the functional limitation merely limits the claimed genus to those sequence variants that ultimately posses the recited activity; it does not establish the Applicant was in possession, as of the effective filing date, of the full genus of structurally diverse erythropoietin variants satisfying that function.
Accordingly, the disclosure of the limited exemplary erythropoietin variants is not considered representative of the full structural breadth encompassed by the “at least 90%” sequence identity limitation, and the rejection under 35 USC 112(a) for lack of written description is maintained.
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, 6-7, 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 (previously cited in prior office action as: PLoS ONE 2013 8(8):e72673 1-7), UniProt (previously cited in prior office action as: P01588 EPO_HUMAN, amino acid sequence last updated: 21 July 1986), and further in view of Wang (previously cited in prior office action as: US 2019/0070307 A1; published: 07 March 2019).
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 claim 1, 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). 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, Uniprot, and Wang.
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]). Zhan’s SEQ ID NO: 122 is 99.8% identical to instant SEQ ID NO: 11:
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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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876
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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.
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 1, 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 1 and 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 1 and 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 sequence-
RKTDHPPGPKPGDCPKCP-
Fc sequence-PPEMLGGPSIFIFPPKPKDTLSISRTPEVTCLVVDLGPDDSDVQITWFVDNTQVYTAKTSPREEQFNSTYRVVSVLPILHQDWLKGKEFKCKVNSKSLPSPIERTISKAKGQPHEPQVYVLPPAQEELSRNKVSVTCLIKSFHPPDIAVEWEITGQPEPENNYRTTPPQLDSDGTYFVYSKLSVDRSHWQRGNTYTCSVSHEALHSHHTQKSLTQSPGK, wherein the further Fc region modification is not shown.
Response to Applicant’s Arguments
Applicant’s arguments concerning the 35 USC 103 rejection over Lu, Zhan, Shi, UniProt, and Wang have been fully considered but are not persuasive.
Applicant argues that one of ordinary skill in the art would not have been motivated to apply the cysteine-to-glycine hinge modification taught by Wang to the feline EPO-Fc fusion protein because Want discusses prevention of an undesirable disulfide bond associated with the spacing between a cysteine near the C-terminus of human EPO and a cysteine of the human IgG1 hinge, whereas Applicant’s feline EPO-Fc construct allegedly possesses different spacing between the corresponding residues.
The argument is not persuasive because the rejection is based on the combined teachings of the references and does not require bodily incorporation of Wang’s human EPO-Fc construct into the feline construct of Lu. Wang expressly teaches an EPO-Fc fusion protein in which the EPO moiety is directly fused to an IgG Fc hinge region and in which a naturally occurring hinge cysteine is substituted with glycine. Wang therefore establishes that cysteine-to-glycine substitution within the Fc hinge was a known modification for directly linked EPO-Fc fusion proteins and that such modified fusion proteins could be successfully produced while retaining EPO biological activity.
Applicant argues that C165R-EPO-Fc resulted in a higher protein yield and the lowest amount of high molecular weight species and presents these results as alleged unexpected results.
There needs to be a nexus between the asserted improvement and the feature relied upon for patentability. The claim contains several variables: any EPO sequence of at least 90% sequence identity to SEQ ID NO:11; C165R mutation; any cat derived IgG Fc region; at least one hinge cysteine-to-glycine substitution; potentially many different hinge configurations; and various Fc mutations. The example cited by the Applicant to show these alleged unexpected results only tested a handful of specific constructs (p. 44, Table 3), not nearly representative of the claimed genus. While the MPEP recognizes that narrow comparative evidence can sometimes support a broader genus, Applicant has not proven a basis for reasonably extrapolating the demonstrated trend. Therefore, the claimed results are not commensurate in scope with the claims.
One of ordinary skill in the art, starting with the feline EPO-Fc fusion taught by Lu, would therefore have recognized the cysteine-to-glycine hinge substation of Wang as a known technique applicable to the same class of EPO-Fc fusion proteins for controlling undesirable cysteine-mediated bonding associated with the hinge region. The fact that Wang discusses a particular spacing relationship in its exemplified human EPO-Fc construct does not negate Wang’s broader teaching that substitution of a hinge cysteine with glycine is suitable in an EPO-Fc fusion protein directly joined through the hinge.
Moreover, claim 1 does not require any particular spacing between the erythropoietin cysteine residue an da hinge cysteine, does not require that the cysteine-to-glycine substitution be made for any particular mechanistic reason, and does not require prevention of the specific disulfide bond discussed by Applicant. Patentability cannot be predicated on such unclaimed distinctions.
Accordingly, when the teachings of Lu, Zhan, Shi, UniProt, and Wang are considered as a whole, the claimed combination would have been obvious to one of ordinary skill in the art.
Claims 18-19, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Lu (previously cited), Zhan (previously cited), Shi (previously cited), UniProt (previously cited), and Wang (previously cited) as applied to claims 1, 4, 6-7, and 28-29 above, and further in view of Brondyk (previously cited as: US 11,498,953 B2; date of patent: 15 November 2022; priority date: 10 July 2020) and Igawa (previously cited as: US 2014/0363428; published: 11 December 2014).
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).
Response to Applicant’s Arguments
Applicant’s arguments have been considered, but are not persuasive because they address Brondyk and Igawa principally with respect to the limitations supplied by the other applied references. The rejection is based on the combined teachings of the references, rather than on any requirement that Brondyk or Igawa independently disclose the complete claimed fusion protein. Brondyk or Igawa are relied upon for the expressly identified Fc substitutions and their known effect on FcRn binding, while the remaining limitations are supplied by the other references set forth in this rejection. Thus, Applicant’s arguments do not identify a deficiency in the combined teachings of the applied references.
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.
US 12,351,622 (date of patent: 08 July 2025)
Claims 1, 4, 6-7, 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 (previously cited), UniProt (previously cited), and Wang (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.
‘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 1 and 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 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 Applicant’s Arguments
As previously addressed, Applicant’s argument that a person of ordinary skill would not be motivated to combine Lu, Zhan, Shi, UniProt, and Wang is not considered persuasive for the reasons set forth above.
Conclusion
Claims 1, 4, 6-7, 18-19, and 27-29 are rejected. No claim is allowed.
THIS ACTION IS MADE FINAL. 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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/JULIA A. ROSSI/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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