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 .
Notice of New Examiner
This case has been transferred to a new examiner for continued examination. Any further communications regarding this case may be directed to the contact information included in the conclusion of this office action.
Election/Restrictions
The reply to the election/restriction requirement filed 18 August 2025 is acknowledged. Applicant elects Group I, claims 1-5 and 10 directed to recombinant proteins, with traverse. Applicant argues that there is not a serious search burden if the restriction is not required (Response to Restriction requirement p. 1). This is not persuasive because search burden is not a factor in the restriction of 371 applications, which use a Unity of Invention standard (See MPEP 1893.03(d) and PCT Rule 13). Applicant further argues that the claimed subject matter is limited to a recombinant protein in which the IFNβ is defined as a C17S-R27T mutein, which is not taught in the cited prior art. The examiner would like to note that for unity of invention, as described in the restriction/election requirement, the common technical feature must be required by all of the claims. Claim 11 is directed towards a method for increasing protein stability during production or isolation and purification of the recombinant protein, wherein a host cell is transformed to express a recombinant protein in which an amino acid at position 17, cysteine of the interferon-beta mutein is modified to another amino acid. Therefore, the common technical feature of the groups is any an antibody-linked IFNβ comprising any mutation of cysteine at position 17. Because the cited art, Kim 2017 (cited in IDS dated 10/28/2022) teaches an antibody-interferon conjugate comprising an R27T mutation, but does not teach a mutation of the amino acid at position 17, the examiner withdraws the restriction requirement.
The restriction requirement as set forth in the Office action mailed on 18 August 2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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 1-2 and 4-6, and 8-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 11 are indefinite for the recitation of an interferon beta mutein which is substituted at particular positions (17 and 27) without any additional structure of the protein recited. The specification teaches (page 5, line 7) that the interferon-beta mutein “may” have the structure of SEQ ID NO:1 but this is not a limiting definition. Thus, the claims encompass a wide variety of IFN-βs not limited to a particular species, isoform, or structure, and therefore does not always possess the exact same residues at the exact same positions. An artisan, therefore, would not be reasonably apprised of the metes and bounds of which residues constitute a mutation at position 17, for example. For example, Uniprot P01577 IFNB3_BOVIN, a full-length bovine interferon beta, and P01574 IFNB_Human, a full-length human interferon beta, both comprise the reside “T” at position 17. It is unclear whether this variant would fall under the scope of the instant “mutein” because it does not have the recited cysteine at position 17. The examiner suggests obviating this rejection by claiming identity to the particular interferon-beta sequence in which position 17 is mutated (e.g. wherein the interferon beta mutein is at least 90% identical to SEQ ID NO: 1).
Claim 11 recites the limitation "the recombinant protein" in line 2. There is insufficient antecedent basis for this limitation in the claim because it is an independent claim that does not previously recite “a recombinant protein”.
Regarding instant claim 15, the metes and bounds of the claims are indefinite. MPEP 2173.05(q) states attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness. Recitation of a use without any active, positive steps delimiting how this use is actually practiced is indefinite.
Claim 16 recites the limitation "the " in line. There is insufficient antecedent basis for this limitation in the claim because it is an independent claim that does not previously recite “a composition”.
Dependent claims are rejected for failing to resolve the indefiniteness as described for claims 1 and 11.
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 1-2 and 4-6, and 8-16 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.
Scope of the claimed genus
Regarding claim 1 and dependents, the claims are broadly directed towards an antibody or any fragment of an antibody directly or indirectly bound to any interferon beta mutein (of any variant or species) wherein a residue at position 17 is substituted with serine and a residue at position 27 is substituted with threonine.
Regarding claim 11 and dependents, the claims are directed towards a method for increasing protein stability during production or isolation and purification a recombinant protein comprising any fragment of an antibody directly or indirectly bound to any interferon beta mutein (of any variant or species wherein a residue at position 17) wherein the cysteine residue at position 17 is modified with any amino acid.
State of the Relevant Art
Regarding antibodies and antibody fragments, Janeway et. al. teaches that antibodies are typically comprised of three equal-sized globular portions joined by a flexible stretch of polypeptide none as the hinge region; two amino-terminal ends formed by the pairing of the variable heavy and variable light chains, and then a C-terminal domain formed by the carboxy-terminal of the heavy chains paired together (Section 3-3. The antibody molecule can be cleaved into functionally distinct fragments, Fig. 3.1b). As described by Fridman, W.H., 1991. Fc receptors and immunoglobulin binding factors 1. The FASEB journal, 5(12), pp.2684-2690, the Fc domain is an immunoglobulin (reads on antibody) portion that binds to or reacts with the Fc receptors (Abstract, p. 2684 left column ¶1- right col. ¶1). Additionally, Chiu et. al. Antibodies 2019 8, 55, 1-80 teaches that the folding of the CDR loops results in a packing of beta sheets that bring the three CDRs of the VH and VL together to form the antigen-binding site (p. 4 Section 1.2.2 The antigen-binding site). The Fv residues in contact with the antigen have been called specificity-determining residues, and antibodies in complex with haptens, proteins, or peptide show distinctive SDR patterns (Section 1.2.2 The antigen-binding site, ¶3), demonstrating that the fragments of an antibody that are “capable of reacting with an antigen to exhibit antigen-binding activity” as defined by the specification may be as small as a single amino acid. While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Regarding immunocytokines, these peptides are also taught generically in the art Borden EC. Interferons α and β in cancer: therapeutic opportunities from new insights. Nat Rev Drug Discov. 2019 Mar;18(3):219-234. doi: 10.1038/s41573-018-0011-2. PMID: 3067980 teaches that “[i]nterferons conjugated to mAbs binding tumour-associated proteins (such as epidermal growth factor receptor (EGFR), HER2 (also known as ERBB2), CD20, CD38, CD138, VEGF receptor (VEGFR) and HLA-DR196,197,198,199,200,201,202,203) may induce direct antiproliferative effects from both the conjugated interferons and the mAb. Clinically, cytokine conjugation with mAbs has been validated by FDA approval of an IL-2 conjugate active in children with refractory or relapsed neuroblastoma204. In murine tumour models of either haematological malignancies or solid tumours, conjugates of mAbs with IFNβ or IFNα2 have yielded greater in vitro and/or in vivo antitumour potency (up to 100 times) than that observed with either mAbs or interferons alone. As an example of effectiveness, compared with anti-EGFR, an immunoconjugate of IFNβ and anti-EGFR suppressed approximately 90% of murine tumours that expressed EGFR, and this suppression was mediated by IFNAR and through a more effective tumour antigen presentation by DCs to CD8+ T cells201. A conjugated mAb mouse IFNα immunocytokine, given 1 day after tumour implantation, prevented growth of human HER2-expressing tumours in 90% of mice; this treatment was effective even when administered after tumours were palpable, albeit significantly less so197” (p. 228 Col. 1-2).
Further, non-native variants of interferon-beta that improve the therapeutic properties are known in the art such as site-specific PEGylation (Lee JI, et. al., Site-specific PEGylation enhances the pharmacokinetic properties and antitumor activity of interferon beta-1b. J Interferon Cytokine Res. 2013 Dec;33(12):769-77. doi: 10.1089/jir.2012.0148. Epub 2013 Aug 20. PMID: 23962003; PMCID: PMC3868373) and targeted mutations (Kay M, et. al. Targeted mutations in Val101 and Arg27 interferon beta protein increase its transcriptional and translational activities. Cytokine. 2016 Feb;78:1-6. doi: 10.1016/j.cyto.2015.11.019. Epub 2015 Nov 23. PMID: 26615566).
Regarding mutations of a cysteine to another amino acid in IFN-β, U.S. 4588585 to Mark et. al. published 13 May 1986 teaches a method for making a synthetic human IFN-β mutein with a mutation to prevent the protein from having an undesirable disulfide link by replacing the cysteine with other amino acids (Col. 2 lines 12-56). Mark et. al. teaches “conversion of cys 17 to neutral amino acids such as glycine, valine, alanine, leucine, isoleucine, tyrosine, phenylalanine, histidine, tryptophan, serine, threonine, and methionine is the preferred approach” and particularly substitution to serine (Col. 4 lines 27-30; Col. 10 lines 34-39), wherein the numbering is according to native human IFN-β.
Summary of Species disclosed in the original specification
The instant specification recites two species of interferon-beta mutein, the human variant of SEQ ID NO: 1, comprising the C17S and R27T mutations, and the IFN-β mutein comprising only R27T (e.g. Example 1-11). There are three species of recombinant protein comprising this muteins, wherein the antibodies are full-length therapeutic monoclonal antibodies trastuzumab, cetuximab, and atezolizumab (Specification, example 2-1).
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for substitution of any recombinant protein comprising any antibody fragment and any interferon-β mutein comprising mutations at positions 17 and 27. There is a lack of an appropriate number of species with identical or alternative amino acid sequences structures of interferon-beta to show which residues are essential to the structure and function of the interferon-beta protein surrounding the recited point mutations. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of interferon-beta muteins and variants. Regarding claims 2, 4-6, and 8-16 the claims are ultimately dependent on the rejected claims 1 or 11 without narrowing the claimed subject matter and thus are also rejected. Regarding claims 3 and 7, the complete amino acid or nucleotide sequence of the recombinant protein is recited, and therefore the claims resolved the written description as described.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
Claims 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
a method of treating a cancer comprising administering an effective amount of the composition of the recombinant protein of claim 1 to a subject having a cancer that expresses a target antigen, and wherein the antibody or antigen-binding fragment comprised by the recombinant protein specifically binds to said target antigen
does not reasonably provide enablement for:
a method of treating any cancer comprising administering an effective amount of the composition of the recombinant protein of claim 1 comprising any antibody or fragment to a subject in need thereof
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application
Scope of the claimed genus and nature of the invention
Claim 16 is broadly directed at a method for treating cancer comprising administering an effective amount of a composition comprising the recombinant protein of claim 1 to any subject in need thereof. Regarding the recombinant protein of claim 1, as described in the written description rejection above, the recombinant protein comprises any antibody or any fragment of an antibody directly or indirectly covalently bound to any interferon-beta mutein in which an amino acid residue at position 17 is substituted with serine and an amino acid residue at position 27 is substituted with threonine.
State of the Relevant Art; level of one of ordinary skill; and level of predictability in the art
The state of the art is described in the written description rejection above.
Regarding immunocytokines, these peptides are also taught generically in the art, such as described for Borden et. al. in the written description rejection above. As noted, Borden et. al. teaches that the immunocytokines showed increased potency compared to antibody or interferons alone, which an artisan may predict would help alleviate the dose-limiting toxicities for the interferons.
Further, non-native variants of interferon-beta that improve the therapeutic properties are known in the art such as site-specific PEGylation (Lee JI et. al.) and targeted mutations (Kay M, et. al.).
Regarding pharmaceutical compositions of interferon-beta and methods of treating cancer with the pharmaceutical compositions, these are known in the art but are limited by their side effects in vivo as discussed above; in particular, Borden et. al. teaches, “Exogenous IFNα2 and IFNβ have also been associated with systemic adverse effects, which are often dose limiting and which have further reduced clinical interest and use. These side effects, which conceivably result in part from immune effector cell activation, include fever and chills with the first injections and fatigue, depression or anorexia with continued administration16,17”, suggesting that the treatment effectiveness of a composition comprising IFNβ would not be predictable unless the systemic effects are reduced by specific targeting of the IFNβ to the cancer (e.g. by an antibody or antigen-binding fragment thereof specific for a target antigen expressed by the cancer).
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make and use the invention based on the content of the disclosure
The specification discloses interferon-[Symbol font/0x62] variant sequences of SEQ ID NO: 1 in which the 17th amino acid residue is substituted with serine and the 27th amino acid residue is substituted with threonine. In addition, the specification also discloses that this substitution thereby comprises a glycosyl group at the 80th and 25th amino acid residues (specification p. 5 para. 2). Regarding methods of treating cancer, the instant specification uses a Trastuzumab-IFN-β-C17S-R27T recombinant protein to target a HER2+ cancer by administering the recombinant protein in a mouse model of human cancer (Fig. 9 and 10). However, the specification does not disclose all possible interferon-[Symbol font/0x62] sequences (including all non-human sequences), wherein a polypeptide comprising a substantive part of the amino acid sequence disclosed in SEQ ID NO: 1 or a polypeptide substantially similar to the polypeptide of a polypeptide comprising no substantive part of the amino acid sequence disclosed in SEQ ID NO: 1 or 15a polypeptide substantially similar to the polypeptide a polypeptide comprising all of the amino acid sequence disclosed in SEQ ID NO: 1 and having human interferon-[Symbol font/0x62] activity. The specification also does not provide a definition of interferon-beta that would limit the claims to a particular species or isoform of interferon-[Symbol font/0x62], or even to naturally occurring or non-synthetic variants of interferon-[Symbol font/0x62].
With the exception of isolated interferon-[Symbol font/0x62] polypeptide with the substitution at wild-type positions C17S and R27T (SEQ ID NO: 1) the skilled artisan cannot envision all the detailed chemical structure of the claimed variant polypeptide, regardless of the complexity or simplicity of the method of isolation.
Regarding the treatment of cancer, the instant specification discloses killing of HER-2 positive cancer cells lines HCC1954 and MDA-MB453 in vitro (Fig. 6); inhibition of cell growth in HER-2 positive cell lines NCI-N87 (high expression); SNU1 and SNU620 (medium expression); and Hs746T and MKN45 (low expression). The effect of the Trastuzumab-IFNβ-C17S-R27T was similar to that of IFNβ R27T alone in the cell lines that had low expression, demonstrating that the effectiveness of the method of treating cancer is related to the target antigen of the recombinant protein being expressed by the cancer. Fig. 9A-B and Fig. 10 demonstrated the anti-cancer effect of Trastuzumab-IFNβ-C17S-R27T in xenograft mouse models of gastric cancer and breast cancer wherein both cancer cell lines express HER2. There is no evidence of record to demonstrate a method of treating cancer with the recombinant protein of the invention, wherein the antibody fragment is not a full-length antigen binding fragment comprising 6 CDRs and wherein patient in need thereof has a cancer that does not express the same target antigen as that bound by the antibody.
Conclusion
The applicant does not have enablement for the complete scope of the method for treating cancer comprising any interferon beta of any sequence or species covalently bound directly or indirectly to an antibody or any fragment of an antibody wherein the subject in need thereof does not necessarily have cancer or a cancer expressing the antigen targeted by the antibody portion of the recombinant protein of claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 15 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claim is directed towards the "use" of the recombinant protein of claim 1 for preparing an anticancer agent. The claims are not directed toward a: 1) composition of matter; 2) machine; 3) manufacture; or 4) process but rather a “use” of a composition of the recombinant protein for preparing an anticancer agent, wherein no active method steps are present to suggest a process is being claimed. "Use" claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101 (MPEP 2173.05(q)).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 4, 5, 10-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chu "Improvement of Purification efficiency by site-directed mutagenesis in interferon beta mutein fusion antibody", Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Pharmacy, Seoul National University (dated 8/2019) (of record, cited in IDS dated 10/10/2023) as evidenced by WO2007110231 to Guyon et. al and WO2016163764 to Shin et. al.
Chu teaches a recombinant protein comprising an interferon-beta mutein and an antibody or fragment thereof “Trastuzumab-C17S-R27T”. Chu et. al. teaches “We also developed a fusion protein of R27T that was fused to the anti-ERBB-2 therapeutic antibody, Trastuzumab. In addition, Trastuzumab-C17S-R27T, in which amino acid cysteine at position 17 of rhIFNβ-1a was replaced with serine, was developed to further improve physical properties and efficacy” (p i-ii).
Regarding claim 2, Chu teaches the recombinant protein is conjugated to human IFN-β wherein there is an additional glycosylation of the 25th amino acid (reads on position 25) by substituting threonine for arginine at position 27 (R27T). As evidenced by WO2007110231 to Guyon et. al., human IFN-β is glycosylated at the asparagine residue at position 80, and as evidenced by WO2016163764 to Shin et. al. R27T results in further glycosylation at position 25 (translation p. 2 ¶5), therefore the conjugate Trastuzumab-C17S-R27T would be glycosylated at positions 25 and 80.
Regarding claim 4, Chu teaches the antibody is Trastuzumab (p i-ii).
Regarding claim 5, Chu teaches that the constructs are fusion protein constructs (p. i-ii, 7-8, 14) and that the fusion protein comprises a linker from the Fc region of the antibody to the interferon (p. 38 ¶2) (reads on peptide linker).
Regarding claims 11-14, teaches a method of production of the Trastuzumab-C17S-R27T in mammalian CHO-S cells (section 3 p. 7, p. 14). Chu teaches that Trastuzumab-C17S-R27T had high efficiency and purity and that the yields were higher for Trastuzumab C17S-R27T for affinity chromatography compared to Trastuzumab-R27T (See Fig. 3).
Claim(s) 11, 13, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by U.S. 7670595 to Gillies et. al. published 2 March 2010 as evidenced by Fridman, W.H., 1991. Fc receptors and immunoglobulin binding factors 1. The FASEB journal, 5(12), pp.2684-2690, the Fc domain is an immunoglobulin.
Claim interpretation: Claim 11 recites a method of increasing protein stability during production or isolation and purification of the recombinant protein, the method comprising: (a) culturing a host cell transformed to express a recombinant protein comprising an antibody or fragment thereof linked directly or indirectly covalently bound to an interferon-beta mutein; and (b) isolating and purifying the recombinant protein from the cultured host cell or a culture product thereof, wherein the host cell is transformed to express the recombinant protein in which an amino acid at position 17, cysteine, of the interferon-beta mutein is modified to another amino acid. Regarding the “antibody or fragment thereof”, the specification recites “The fragments of the antibody represent specific sites capable of reacting with an antigen to exhibit antigen-binding activity, and may include, for example, a Fab fragment (fragment by papain digestion), a Fab' fragment (fragment by pepsin digestion and partial reduction), a F(ab')2 fragment (fragment by pepsin digestion), a Facb (fragment by plasmin digestion), a Fd (fragment by pepsin digestion, partial reduction and reaggregation), a scFv fragment (fragment by molecular biology technique), and the like” (Specification p. 5 lines 18-24). The examples do not represent a closed definition, therefore the only requirement of the fragment based on the specification is that it is a “specific site capable of reacting with an antigen to exhibit antigen-binding activity”. The broadest reasonable interpretation of the claim, then, is that it requires the method comprising an interferon-beta mutein with a mutation at position 17 covalently linked, directly or indirectly, to a fragment of an antibody that is capable of reacting with an antigen.
Regarding claims 11 and 13, Gillies et. al. teaches “methods for the production, secretion, and purification of recombinant variant of immunoglobulin Fc-IFN-betasol fusion proteins” (Col. 6 lines 52-54); “Another embodiment of the invention includes nucleic acid sequences encoding Fc-IFN-.betasol variants with at least one codon substitution in the mature human IFN-.beta. protein sequence. In one embodiment, a codon substitution replaces the cysteine corresponding to position 17 in the mature human IFN-.beta. sequence with a serine (C17S). Expression of this nucleotide sequence, contained on an appropriate plasmid, in a mammalian cell culture system resulted in the efficient production of the fusion protein huFc-huIFN-.betasol(C17S)” (Col. 8 lines 49-58) (reads on culturing host cells transformed with the recombinant protein). Gillies et. al. teaches “Another useful property of Fc-X fusion proteins is that the Fc portion generally has the effect of increasing protein production significantly. This is believed to occur, in part, because the Fc moiety of the fusion protein, commonly referred to as the expression cassette, is designed for efficient secretion of the fusion protein and, in part, because the fusion proteins can be produced in and secreted from host mammalian cells that naturally express immunoglobulin such that the fusion protein is readily secreted from the host cell” (Col. 6 lines 20-28). Gillies et. al. teaches that the point mutation C17S restores correct folding of the Fcgamma-IFN-beta fusion protein (Col. 9 lines 51-58) and that more of the C17S fusion protein was non-aggregated after purification (reads on isolating and purifying the recombinant protein) (Col. 9 lines 59-65). As evidenced by Fridman, W.H., 1991. Fc receptors and immunoglobulin binding factors 1. The FASEB journal, 5(12), pp.2684-2690, the Fc domain is an immunoglobulin (reads on antibody) portion that binds to or reacts with the Fc receptors (Abstract, p. 2684 left column ¶1- right col. ¶1).
Regarding claim 14, Gillies teaches that the Fc-IFN-β fusion protein is prepared in mammalian cells (Col. 3 line 58- Col. 4 line 8; Col. 9 lines 44-46).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim 1-10 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO2016140528 to Shin et. al. (hereinafter "Shin et. al. A") published September 9 2016 in view of Runkel, et al. Structural and functional differences between glycosylated forms of human interferon-β (IFN-β). Pharmaceutical Research (1998), 15:4, p.641-649 and U.S. 7670595 to Gillies et. al. published 2 March 2010 as evidenced by WO2007110231 to Guyon et. al.; WO2016163764 to Shin et. al. (hereinafter “Shin et. al. B”); and Bioinformatics.org “Sequence Manipulation Suite: Reverse Translate”, available at www.bioinformatics.org/sms2/rev_trans.html, published 2004.
Shin et. al. A is directed towards immunocytokines in which a human interferon-beta variant is conjugated to an antibody, wherein the immunocytokine can be favorably used as a target therapeutic agent for multiple sclerosis or cancer since the immunocytokine specifically targets the anti-cancer activity of IFN-β to the target tissue (e.g. cancer) using the antigen-binding of the antibody (Translation p. 001-002).
Regarding claims 1, 4, and 9 Shin et. al. A teaches the anti-HER2 antibody heavy chain trastuzumab (HERCEPTIN®) linked to human interferon-beta or variants of interferon-beta by an indirect covalent bond through a peptide linker (Fig. 10B, translation p. 005 bottom para., p. 008 bottom para., and p. 011 Example 7). Shin et. al. A teaches peptide sequences SEQ ID NO: 16 and 17 which comprise the heavy chain of trastuzumab (as evidenced by the instant specification SEQ ID NO: 3, reads on instant claim 4) and an interferon-beta variant. Shin et. al. A teaches that the interferon variant is SEQ ID NO: 2, which comprises the R27T mutation. Shin et. al. A further teaches that the variants interferon-beta has increased activity or function compared to wildtype interferon-beta and that the antibody-interferon-beta fusion can be used for the target treatment of disease in order to protect normal tissue from toxic effect (p. 003, middle). Shin et. al. A teaches that the immunocytokine with the R27T variant result in increased amount of expression in CHO cells compared with a wild type immunoglobulin conjugated to human interferon (Example 2, translation p.009, Fig. 1).
SEQ ID NO: 2 of Shin et. al. A is 99.4% identical to instant SEQ ID NO: 1 as shown below:
Query Match 99.4%; Score 864; Length 166;
Best Local Similarity 99.4%;
Matches 165; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MSYNLLGFLQRSSNFQSQKLLWQLNGTLEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIY 60
|||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||
Db 1 MSYNLLGFLQRSSNFQCQKLLWQLNGTLEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIY 60
Qy 61 EMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSL 120
Qy 121 HLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRLTGYLRN 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 HLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRLTGYLRN 166
Regarding claim 5, Shin et. al. A teaches that the antibody or fragment is linked to the IFN-beta by a peptide linker (p. 006, para. 6-13). SEQ ID NOs: 16 and 17 also comprise a peptide linker between the antibody and IFN-beta sequences.
Shin et. al. A does not teach an antibody comprising an interferon-beta variant wherein the interferon-beta variant comprises “an amino acid residue at position 17” “substituted with serine”.
Regarding claim 6 and 8, Shin et. al. A teaches a polynucleotide sequence encoding the immune cytokine of the invention and an expression vector comprising the polynucleotide (translation p. 007, top).
Regarding claim 9, Shin et. al. A teaches host cells transformed with the vector (translation p. 007, middle).
Regarding claim 10, Shin et. al. A teaches an experiment wherein the immunocytokine was treated on a cell culture solution at a concentration of 10 to 10000 ng/mL and then cultured for 24 hours or 48 hours. This is inherently a pharmaceutical composition because it requires the immunocytokine in a saline or buffer solution compatible with the culture of living cells, thereby disclosing a composition of the immunocytokine and the saline or buffer.
The inclusion of serine at position 17 (C17S) is resolved by Runkel et. al. and Gillies et. al.
Runkel teaches glycosylated IFN-β (i.e., IFN-β-1a) and unglycosylated IFN-β (i.e., IFN-β-1b) proteins and that the glycosylation of IFN-β contributes to activity and reduced thermal denaturation sensitivity; whereas, unglycosylated forms produced more aggregates and reduced anti-viral activity (abstract). Runkel also teaches the addition of the C17S mutation which results in increased yield of biologically active IFN-β (p.1, col.2, para.1). Runkel also teaches that human IFN-β has three cysteine residues that can form disulfide bonds, and that denaturation, and thus aggregation, in the C17S mutant may be reduced because disulfide scrambling is likely reduced in the mutant (p.8, col.1, para.2). Runkel et. al. further teaches a form of IFN-β-1a (the glycosylated form) comprising the Ser-17 mutation and that glycosylation of the Ser-17 mutant form restored anti-viral activity (p. 2 right col ¶1, Fig. 3).
Likewise, Gillies et. al. also points to advantages of the C17S mutation. Gillies et. al. teaches that the point mutation C17S restores correct folding of the Fcgamma-IFN-beta fusion protein (Col. 9 lines 51-58) and that more of the C17S fusion protein was non-aggregated after purification when expressed in mammalian tissue culture (reads on isolating and purifying the recombinant protein) (Col. 9 lines 59-65).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Shin, Runkel, and Gillies by modifying the R27T mutant that has increased glycosylation (as taught by Shin) to have an additional C17S mutation (as taught by Runkel and Gillies) to arrive at the instantly claimed invention, in order to receive the added expected benefit (as taught by Runkel and Gillies) that the C17S substitution results in less denaturation and aggregation of the protein in order to improve the glycosylated trastuzumab-IFN-β R27T with the improved folding and reduced aggregation demonstrated by the Fc-IFN-β C17S fusion proteins of Gillies. One of ordinary skill in the art would have a reasonable expectation of success because Shin, Runkel, and Gillies teach that the R27T and C17S mutations contribute to enhanced stability, which would predictably result in higher yield and increased activity of the antibody fragment-IFN-β protein.
Regarding claim 2, as evidenced by WO2007110231 to Guyon et. al., human IFN-β is glycosylated at the asparagine residue at position 80 and as evidenced by WO2016163764 to Shin et. al. R27T results in further glycosylation at position 25 (translation p. 2 ¶5).
Regarding claim 3, the substitution of C17S in SEQ ID NO: 2 as taught by Shin et. al. (modified Shin et. al. as described above) would result in a sequence 100% identical to instant SEQ ID NO: 1.
Regarding claim 7, the claim is directed towards a polynucleotide encoding the recombinant protein comprising the interferon-beta mutein and the antibody or fragment thereof, “wherein the polynucleotide is defined by a nucleotide sequence of SEQ ID NO: 9, 10 or 11”. The broadest reasonable interpretation of claim 7, therefore, is that the polynucleotide may be defined by any nucleotide sequence of SEQ ID NO: 9, 10, or 11 or in other words, the nucleotide sequence may be defined as any fragment of SEQ ID NOs: 9, 10, or 11. A described above, modified Shin et. al. would result in a sequence 100% identical to SEQ ID NO: 1. Shin et. al. teaches polynucleotides encoding the immunocytokine comprising SEQ ID NO: 1. As evidenced by Bioinformatics.org “Sequence Manipulation Suite: Reverse Translate”, available at www.bioinformatics.org/sms2/rev_trans.html, published 2004, the polynucleotide encoding SEQ ID NO: 1 with the most common amino acids is 18.5% match and has 81.5% local similarity to instant SEQ ID NO: 9 as shown below:
RESULT 1
NASEQ2_09192025_135938
Query Match 18.5%; Score 350.8; DB 1; Length 498;
Best Local Similarity 81.5%;
Matches 406; Conservative 0; Mismatches 92; Indels 0; Gaps 0;
Qy 1396 ATGTCCTACAACCTGCTGGGCTTCCTGCAGCGGTCCTCCAACTTCCAGTCCCAGAAACTG 1455
||| ||| |||||||||||||| |||||||| | |||||| ||| ||||||||||
Db 1 ATGAGCTATAACCTGCTGGGCTTTCTGCAGCGCAGCAGCAACTTTCAGAGCCAGAAACTG 60
Qy 1456 CTGTGGCAGCTGAATGGCACCCTGGAATACTGCCTGAAGGACCGGATGAACTTCGACATC 1515
|||||||||||||| |||||||||||||| |||||||| || || |||||||| || ||
Db 61 CTGTGGCAGCTGAACGGCACCCTGGAATATTGCCTGAAAGATCGCATGAACTTTGATATT 120
Qy 1516 CCCGAGGAAATCAAGCAGCTGCAGCAGTTCCAGAAAGAGGACGCCGCTCTGACCATCTAC 1575
|| || ||||| || |||||||||||||| |||||||| || || || |||||||| ||
Db 121 CCGGAAGAAATTAAACAGCTGCAGCAGTTTCAGAAAGAAGATGCGGCGCTGACCATTTAT 180
Qy 1576 GAGATGCTGCAGAACATCTTCGCCATCTTCCGGCAGGACTCCTCCTCCACCGGCTGGAAC 1635
|| |||||||||||||| || || || || || ||||| | | |||||||||||||
Db 181 GAAATGCTGCAGAACATTTTTGCGATTTTTCGCCAGGATAGCAGCAGCACCGGCTGGAAC 240
Qy 1636 GAGACAATCGTGGAAAATCTGCTGGCCAACGTGTACCACCAGATCAACCACCTGAAAACC 1695
|| || || |||||||| |||||||| |||||||| || ||||| ||||| |||||||||
Db 241 GAAACCATTGTGGAAAACCTGCTGGCGAACGTGTATCATCAGATTAACCATCTGAAAACC 300
Qy 1696 GTGCTGGAAGAGAAGCTGGAAAAAGAGGACTTCACCCGGGGCAAGCTGATGTCCTCCCTG 1755
||||||||||| || ||||||||||| || || ||||| ||||| |||||| | ||||
Db 301 GTGCTGGAAGAAAAACTGGAAAAAGAAGATTTTACCCGCGGCAAACTGATGAGCAGCCTG 360
Qy 1756 CACCTGAAGCGGTACTACGGCCGGATCCTGCACTACCTGAAGGCCAAAGAATACTCCCAC 1815
|| ||||| || || || ||||| || ||||| || ||||| || |||||||| |||
Db 361 CATCTGAAACGCTATTATGGCCGCATTCTGCATTATCTGAAAGCGAAAGAATATAGCCAT 420
Qy 1816 TGCGCCTGGACCATCGTGCGGGTGGAAATCCTGCGGAACTTCTACTTTATCAACCGGCTG 1875
||||| |||||||| ||||| |||||||| ||||| ||||| || ||||| ||||| |||
Db 421 TGCGCGTGGACCATTGTGCGCGTGGAAATTCTGCGCAACTTTTATTTTATTAACCGCCTG 480
Qy 1876 ACCGGCTACCTGAGGAAC 1893
|||||||| ||| | |||
Db 481 ACCGGCTATCTGCGCAAC 498
The reverse translation of SEQ ID NO: 1 therefore comprises at least a fragment and therefore reads on a nucleotide sequence of SEQ ID NO: 9.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over U.S. 7670595 to Gillies et. al. published 2 March 2010 as applied to claim 11 above, and further in view of WO2016163764 to Shin et. al. published 13 October 2016 (hereinafter “Shin B”).
The teachings of Gillies et. al. in regards to claim 11 are in the 102 rejection above. Gillies et. al. does not teach the method of isolation and purification of a recombinant protein comprising an antibody or fragment thereof covalently bound to an interferon-beta mutein comprising a mutation of cysteine at position 17 and wherein the interferon-beta mutein is an R27T mutein of interferon-beta. This deficiency is resolved by Shin B.
Shin B teaches a mutein of interferon B that is stabilized by an R27T mutation (R27T). Shin et. al. teaches that the R27T mutation introduces further glycosylation at position 25 resulting in increased stability, decreased protein aggregation tendency, and increase half-life when compared to wild-type IFN-β1a.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to modify the method of producing an Fc-IFN-β-C17S fusion protein conjugate with the R27T mutation in order to benefit from the increased stability, decreased aggregation, and increased half-life as taught by Shin B. One of ordinary skill in the art would have a reasonable expectation of success because Shin and Gillies teach that the R27T and C17S mutations, respectively, contribute to enhanced stability, which would predictably result in higher yield and increased activity of the antibody-IFN-β protein.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over WO2016140528 to Shin et. al. published September 9 2016 (hereinafter Shin et. al. A); Runkel, et al. Structural and functional differences between glycosylated forms of human interferon-β (IFN-β). Pharmaceutical Research (1998), 15:4, p.641-649; and U.S. 7670595 to Gillies et. al. published 2 March 2010 as applied to claim 1 above, and further in view of Yang X, et. al. Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell. 2014 Jan 13;25(1):37-48. doi: 10.1016/j.ccr.2013.12.004. PMID: 24434209; PMCID: PMC3927846.
The teachings of Shin A, Runkel et. al., and Gillies et. al. as applied to claim 1 are in the 103 rejection above.
Shin A further teaches that the antibody-IFN-β mutein of the invention has superior interferon activity to natural interferon-beta and the characteristic of recognize a specific antigen, it is useful for treatment of disease such as multiple sclerosis and cancer (translation p. 003 ¶9, p.005, p. 011).
Shin et. al. A does not teach a method for treating cancer comprising administering an effective amount of the composition comprising the recombinant protein of claim 1 to a subject in need thereof. This deficiency is resolved by Yang et. al.
Yang et. al. teach administration of an anti-Neu-IFNβ to a mouse model of HER-2 positive cancer. Yang et. al. teaches that “Anti-tumor immunity mediated by anti-Neu Ab treatment is reduced in neu Tg mice, as high Neu expression (as self and tumor-associated antigens) in all mammary glands tolerizes host immune cells during early life due to the nature of transgene expression. The NEUOT-I/OT-II transgenic mice model, in which oncogenic rat neu is highly expressed in both mammary tumor and normal mammary gland, is an important model for monitoring the T cell response during spontaneous tumor development and adoptive transfer cancer therapy (Wall et al., 2007; Yang et al., 2009). NOP23 is one of the Neu+ mammary tumor cell lines generated from NEUOT-I/OT-II transgenic mice (Yang et al., 2009). Here we use NOP23 tumor bearing NEUOT-I/OT-II transgenic mice as a Neu-tolerized host model. Impressively, anti-Neu-IFNβ more profoundly inhibited tumor growth than anti-Neu Ab alone even in a tolerized model (Figure 2D)” (p. 4 para. 2).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the trastuzumab-IFN-β-mutein comprising C17S and R27T mutations as taught by modified Shin A in view of Runkel et. al. and Gillies et. al. for the anti-Neu-IFNβ conjugate of Yang et. al. in order to benefit from the improved physical properties and enhanced stability of the modified Shin A immunocytokine in order to better treat the cancer in the method of administering to a subject as taught by Yang et. al. This would have a reasonable expectation of success because an artisan would expect an immunocytokine with better IFN-β activity and higher stability to have an improved anti-cancer effect.
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 o