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 1-30 and 36-37 have been cancelled and claims 31, 38, 40, 45, and 47 have been amended, as requested in the amendment filed on 12/11/2025. Following the amendment, claims 31-35 and 38-47 are pending in the instant application.
Claims 31-35 and 38-47 are under examination in the instant office action.
It is specifically noted that Applicant has amended independent claim 31 such that the claim scope has changed; claim 31 has been amended such that the recited stabilizer comprises “an amino acid or amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine” and this scope is narrower than the previously recited stabilizer comprising “i) an amino acid or an amino acid derivative, or ii) a sugar alcohol, or a mixture thereof”. As such, the change in claim scope necessitates the new grounds of rejection detailed below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/08/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification - Objection Withdrawn
The specification was objected to for including trade names or marks used in commerce. Applicant indicated on Page 6 of Remarks (12/11/2025) that the indicated term KEVZARA and BRIJ are properly represented. Upon further review, it is acknowledged that KEVZARA and BRIJ are properly represented in the Appendix to the Specification submitted 02/27/2023. Thus, the objection to the specification is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 45 and 47 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the recitation of “configured for”. Applicant has amended claim 45 to recite that "the stable pharmaceutical formulation is suitable for dilution prior to intravenous administration," and claim 47 has been amended to recite that "the stable pharmaceutical formulation is suitable for intravenous or subcutaneous administration." As such, the claims are now considered to be clear and definite and the rejection of claims 45 and 47 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim Rejections - 35 USC § 102 - Withdrawn
Claims 31-36, 39, 42-43, and 46-47 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by KR 20150055107 A (previously cited on PTO-892; translation of the description previously provided; herein after referred to as "Bao").
Applicant has amended independent claim 31 such that the claim now requires the limitation of “a stabilizer comprising an amino acid or amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine”. Applicant argues on Pages 7-8 of Remarks that Bao does not describe, expressly or inherently, "a stabilizer comprising an amino acid or an amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine" as recited in amended claim 31. Additionally, claim 36 has been cancelled. Thus, in view of the above, the rejection of claims 31-36, 39-40, 42-43, and 46-47 under 35 U.S.C. 102(a)(1) as being anticipated by Bao is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claim 40 was rejected under 35 U.S.C. 103 as being unpatentable over KR 20150055107 A (previously cited on PTO-892; translation of the description previously provided; herein after referred to as "Bao").
Applicant has amended independent claim 31, from which claim 40 depends, and claim 40 such that the claims now require the limitation of “a stabilizer comprising an amino acid or amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine”. Bao alone does not describe, expressly or inherently, "a stabilizer comprising an amino acid or an amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine" as recited in amended claims 31 and 40. Thus, in view of the instant claim amendments, the rejection of claim 40 under 35 U.S.C. 103 as being unpatentable over Bao is withdrawn.
Claim 37 was rejected under 35 U.S.C. 103 as being unpatentable over KR 20150055107 A (previously cited on PTO-892; translation of the description previously provided; herein after referred to as "Bao") and in further view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claim 37 has been cancelled, rendering the rejection moot. As such, the rejection of claim 37 under 35 U.S.C. 103 as being unpatentable over Bao and Liu is withdrawn.
Double Patenting - Withdrawn
Claims 36-37 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-15, 17-18, 23-24, and 26-27 of copending Application No. 18/434,346 (herein after referred to as "reference application") in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 36-37 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9-11, 13-21, 26, 29, 31, 33, and 43-44 of copending Application No. 18/019,020 (herein after referred to as "second reference application") in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 36-37 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 8-9, 11-12, and 14-18 of copending Application No. 18/593,012 (herein after referred to as "third reference application") in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
It is noted that the recitation of 18/539,012 in the previous Office Action was a typographical error, which has been corrected herein to recite 18/593,012.
Claims 36-37 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 8-11, and 13-20 of U.S. Patent No. 10,980,881 (herein after referred to as “first reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
It is noted that the recitation of 10,981,881 in the previous Office Action was a typographical error, which has been corrected herein to recite 10,980,881.
Claims 36-37 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-13, 15-19, 21-22, 24-25 of U.S. Patent No. 11,730,698 (herein after referred to as “second reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 36-37 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 8-14 of U.S. Patent No. 11,951,207 (herein after referred to as “third reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 36-37 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-9, and 11-14 of U.S. Patent No. 11,986,523 (herein after referred to as “fourth reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 36-37 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-9 of U.S. Patent No. 12,065,482 (herein after referred to as “fifth reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
As noted above, claims 36-37 have been cancelled, rendering the above-listed claim rejections under nonstatutory double patenting moot. Thus, the above-listed claim rejections under nonstatutory double patenting are withdrawn.
Claim Rejections - 35 USC § 103 - New
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.
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 31-35, 39-40, 42-44, and 46-47 are rejected under 35 U.S.C. 103 as being unpatentable over KR 20150055107 A (previously cited on PTO-892; translation of the description previously provided; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
With regard to claims 31-34, the invention of Bao provides therapeutic antibody preparations used in accordance with the invention may be prepared by combining an antibody having the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer which may be lyophilized formulations or aqueous solutions (Page 15, Pharmaceutical Formulation). In one embodiment, the formulation is an anti-IL-6R antibody-containing liquid formulation which comprises a high concentration of anti-IL-6R antibody and may further comprise (i) one or more amino acids as a stabilizer (e.g., arginine and/or methionine), (ii) a buffering agent (e.g., histidine), (iii) one or more surfactants (Page 17). With regard to the stabilizer of Bao, it is noted that “stabilizer” is defined as an excipient that stabilizes a pharmaceutical formulation, or a mixture of two or more excipients wherein, for example, stabilizers can prevent instability due to freeze-thaw or other heat induced destabilization and exemplary excipients herein include surfactants and amino acids such as arginine or methionine (including derivatives thereof) (Page 13; emphasis added). Bao further discloses acceptable carriers, excipients, and stabilizer that are nontoxic to recipients including, for example, antioxidants (e.g., ascorbic acid and methionine) and amino acids (e.g., glycine, glutamine, asparagine, histidine, arginine or lysine) (Page 15). It is further noted, that according to such an embodiment the IL-6R antibody can be tocilizumab (Id.) wherein the hypervariable regions (i.e., CDRs) of tocilizumab are represented by SEQ ID NOs: 3-5 (light chain CDRs 1-3) and SEQ ID NOs: 6-8 (heavy chain CDRs 1-3) (Page 8); Bao SEQ ID NO:s 3-8 are 100% matches to instant SEQ ID NOs: 1-6, respectively. Bao provides the amino acid sequences corresponding to the light chain and heavy chain of tocilizumab in SEQ ID NOs: 1 and 2, respectively (Page 5; FIGS 7A/B). It is specifically noted that residues 1-107 of Bao SEQ ID NO: 1 are a 100% match to instant SEQ ID NO:7 and residues 1-119 of Bao SEQ ID NO: 2 are a 100% match to instant SEQ ID NO: 8.
Bao does not explicitly teach/suggest a stabilizer comprising an amino acid or an amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine.
Liu teaches highly concentrated protein or antibody formulations that are stable, and of low viscosity and turbidity (Paragraph 0011). In one embodiment, the invention concerns highly
concentrated antibody formulations of low turbidity comprising protein or antibody (100-260 mg/ml), histidine (10-100 mM), arginine-HCl (50-200 mM) and polysorbate (0.01 %-0.1 %), having a pH of 5.5-7.0, a viscosity of 50 cs or less and osmolarity from 200 mOsm/kg-450 mOsm/kg (Paragraph 0012). The protein to be formulated is generally present in solution; for example, in the elevated ionic strength reduced viscosity formulations of the invention, the protein may be present in a pH-buffered solution at a pH from about 4-8, and preferably from about 5-7, wherein the buffer concentration can be from about 1 mM to about 20 mM, alternatively from about 3 mM to about 15 mM, depending, for example, on the buffer and the desired tonicity of the formulation (e.g., of the reconstituted formulation) (Paragraph 0199). In a preferred embodiment, it may be desirable to add a surfactant to the pre-lyophilized formulation and/or the surfactant may be added to the lyophilized formulation and/or the reconstituted formulation; the amount of surfactant added is such that it reduces particulate formation of the reconstituted protein and minimizes the formation of particulates after reconstitution wherein the surfactant may be present in the pre-lyophilized formulation in an amount from about 0.001-0.5% (Paragraph 0202). Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers; acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers, antioxidants including ascorbic
acid, methionine, Vitamin E, sodium metabisulfite; preservatives, isotonicifiers, stabilizers, metal complexes (e.g., Zn-protein complexes); chelating agents such as EDTA and/or non-ionic surfactants (Paragraph 0212; emphasis added). Additional excipients include agents which can serve as one or more of the following: (1) bulking agents, (2) solubility enhancers, (3) stabilizers and (4) agents preventing denaturation or adherence to the container wall; such excipients include: polyhydric sugar alcohols and amino acids such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, omithine, leucine, 2-phenylalanine, glutamic acid, threonine, etc. (Paragraph 0217; emphasis added). Thus, Liu suggests concerns highly
concentrated aqueous/liquid antibody formulations comprising protein or antibody, a buffer, and pharmaceutically acceptable carriers, excipients, and/or stabilizers with optimized properties including: (i) low turbidity, (ii) optimized pH for therapeutic stability/effectiveness, (iii) optimized tonicity to lessen protein/antibody intra- and inter-molecular interactions, (iv) optimum solubility, (v) reduced agitation-induced protein/antibody aggregation (see, for example, Paragraphs 0212-0219).
Thus, as evidenced by the references, it is noted that the identity and working concentrations of antibody formulation (e.g., high concentration antibody formulation) components such as carriers, excipients, and/or stabilizers (i.e., buffers/buffering agents, stabilizers, surfactants, etc.) are recognized as antibody formulation variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of antibody formulation (e.g., high concentration antibody formulation) components such as carriers, excipients, and/or stabilizers (i.e., buffers/buffering agents, stabilizers, surfactants, etc.) would be seen as routine optimization.
It would have been prima facie obvious to one of ordinary skill in the art at the time the
invention was filed to develop a high concentration aqueous/liquid antibody formulation comprising an antibody that binds to an interleukin-6 receptor, a surfactant, a stabilizer (comprising an amino acid or amino acid derivative wherein the amino acid or amino acid derivative is a mixture of threonine and methionine; it is specifically noted that the “comprising” language of the instant claims does not exclude additional stabilizer agents such as, for example, arginine), and a buffer wherein the antibody or antigen binding fragment thereof comprises light chain CDRs 1-3, heavy chain CDRs 1-3, light chain variable, and heavy chain variable sequences corresponding to (SEQ ID NOs: 1-3, 4-6, 7, and 8, respectively) wherein one of ordinary skill in the art would have been motivated to optimize the properties of said formulation (e.g., tonicity, turbidity, stability, solubility, therapeutic effectiveness, etc.) are optimized for therapeutic applications, as suggested by both Bao and Liu. One of ordinary skill in the art would have a reasonable expectation of success because both Bao and Liu disclose stable, high-concentration antibody formulations wherein said formulations may comprise buffers, stabilizers, and surfactants as components, and both Bao and Liu indicate that the identity and working concentrations of antibody formulation (e.g., high concentration antibody formulation) components such as carriers, excipients, and/or stabilizers (i.e., buffers/buffering agents, stabilizers, surfactants, etc.) are recognized as antibody formulation variables which achieve a recognized result (i.e., optimized formulation properties). As such, from the teachings of Bao and Liu, one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
With regard to claim 35, Bao further teaches that the anti-IL-6R antibody-containing liquid formulation according to the invention comprises a high concentration of anti-IL-6R antibody, preferably 50 to 300 mg/mL (Page 16). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 39-40, Bao further teaches concentrations for each component: the anti-IL-6R antibody-containing liquid formulation according to the invention comprises a high concentration of anti-IL-6R antibody, preferably 50 to 300 mg/mL (Page 16); amino acids as stabilizers may be present at a concentration between 50 to 1,500 mM wherein if the antibody-containing liquid preparation according to the invention contains arginine but not methionine, the concentration of arginine is preferably 50 to 1,500 mM and if the antibody-containing liquid preparation according to the present invention contains arginine and methionine, the total concentration of arginine and methionine is preferably 50 to 1,200 mM wherein, for example, the arginine concentration is 40 to 1,000 mM and methionine concentration is 10 to 200 mM (Page 16); the concentration of the buffer solution is generally 1 to 500 mM and if histidine buffer is used, the buffer preferably contains histidine at a concentration of 5 to 25 mM (Page 16); and the amount of surfactant(s) added to the antibody preparation according to the invention is generally from 0.0001 to 10% (w/v) (Page 17 ). Bao also teaches that the pH of the formulation in the high concentration antibody-containing liquid formulation according to the invention is preferably 5 to 7 (Page 16). Furthermore, Liu teaches that in one embodiment, the invention concerns highly
concentrated antibody formulations of low turbidity comprising protein or antibody (100-260 mg/ml), histidine (10- 100 mM), arginine-HCl (50-200 mM) and polysorbate (0.01 %-0.1 %), having a pH of 5.5-7.0, a viscosity of 50 cs or less and osmolarity from 200 mOsm/kg-450 mOsm/kg (Paragraph 0012). The protein to be formulated is generally present in solution; for example, in the elevated ionic strength reduced viscosity formulations of the invention, the protein may be present in a pH-buffered solution at a pH from about 4-8, and preferably from about 5-7, wherein the buffer concentration can be from about 1 mM to about 20 mM, alternatively from about 3 mM to about 15 mM, depending, for example, on the buffer and the desired tonicity of the formulation (e.g., of the reconstituted formulation) (Paragraph 0199). In a preferred embodiment, it may be desirable to add a surfactant to the pre-lyophilized formulation and/or the surfactant may be added to the lyophilized formulation and/or the reconstituted formulation; the amount of surfactant added is such that it reduces particulate formation of the reconstituted protein and minimizes the formation of particulates after reconstitution wherein the surfactant may be present in the pre-lyophilized formulation in an amount from about 0.001-0.5% (Paragraph 0202).
Thus, as evidenced by the references, it is noted that the identity and working concentrations of antibody formulation (e.g., high concentration antibody formulation) components such as carriers, excipients, and/or stabilizers (i.e., buffers/buffering agents, stabilizers, surfactants, etc.) are recognized as antibody formulation variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of antibody formulation (e.g., high concentration antibody formulation) components such as carriers, excipients, and/or stabilizers (i.e., buffers/buffering agents, stabilizers, surfactants, etc.) would be seen as routine optimization. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 42 and 46, Bao further teaches an embodiment wherein the pH for stabilizing tocilizumab SC vial 162 mg (single unit dose) was found to be approximately pH 6.0 and as such buffering agent L-histidine/L-histidine monohydrochloride was added at a concentration of 20 mM and pH 6.0 achieved by using buffer salts and bases; polysorbate 80 was added at a concentration of 0.2 mg/mL as a stabilizer to prevent potential mechanical stress (stirring) induction of proteins and potential freezing and thawing inducing destabilization; L-arginine hydrochloride and L-methionine were added at concentrations of 100 mM and 30 mM, respectively, as stabilizers to prevent potential thermal stress induced destabilization of the protein (Pages 28-29). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 43-44 and 47, Bao further teaches subcutaneously administering an anti-IL-6 receptor (IL-6R) antibody to a patient, wherein the anti-IL-6R antibody is administered at a fixed dose of 162 mg per dose (e.g., weekly, every two weeks or every ten days) (Page 17) wherein the SC fixed dose may be formulated as detailed above. Examples of IL-6 mediated disorders to be treated are listed on pages 17-18, wherein in one embodiment, the method comprises subcutaneously administering tocilizumab to the patient, wherein the patient has rheumatoid arthritis, and wherein tocilizumab is administered at a fixed dose of 162 mg per dose every week or every two weeks (Page 18). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claim Rejections - 35 USC § 103 - Maintained
Claims 38, 41, and 45 stand as rejected under 35 U.S.C. 103 as being unpatentable over KR 20150055107 A (herein after referred to as "Bao") in view of US 2004/019324 A1 (herein after referred to as "Liu").
Double Patenting - Maintained
Claims 31-35 and 38-47 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-15, 17-18, 23-24, and 26-27 of copending Application No. 18/434,346 (herein after referred to as "reference application") in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9-11, 13-21, 26, 29, 31, 33, and 43-44 of copending Application No. 18/019,020 (herein after referred to as "second reference application") in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 8-9, 11-12, and 14-18 of copending Application No. 18/593,012 (herein after referred to as "third reference application") in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 8-11, and 13-20 of U.S. Patent No. 10,980,881 (herein after referred to as “first reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-13, 15-19, 21-22, 24-25 of U.S. Patent No. 11,730,698 (herein after referred to as “second reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 8-14 of U.S. Patent No. 11,951,207 (herein after referred to as “third reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-9, and 11-14 of U.S. Patent No. 11,986,523 (herein after referred to as “fourth reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Claims 31-35 and 38-47 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-9 of U.S. Patent No. 12,065,482 (herein after referred to as “fifth reference patent”) in view of KR 20150055107 A (previously cited on PTO-892; herein after referred to as "Bao") in view of US 2004/019324 A1 (previously cited on PTO-892; herein after referred to as "Liu").
Response to Arguments
With regard to claim rejections in view of Bao and/or Liu, Applicant argues the following on Pages 9-19 of Remarks:
Experimental Example 4-1, a formulation comprising threonine 300 mM, a formulation comprising taurine 300 mM, and a formulation comprising a mixture of threonine 200 mM and methionine 100 mM (Examples 14-16) were prepared in histidine buffer. Under initial conditions, the formulation including the threonine/methionine mixture exhibited a higher content of intact immunoglobulin G (Intact IgG¾) (98.06%) than the formulations including taurine or threonine alone (97.77% and 97.49%, respectively), while maintaining comparable main peak% and low levels of high-molecular-weight species (see Application As-Filed, [02l5]). Experimental Examples 4-2 to 4-5 further show that formulations containing threonine/methionine mixtures across a range of stabilizer, buffer, antibody concentrations and pH values have high initial Intact IgG% (e.g., 99.72-99.81% in Examples 17-22), maintain Intact IgG% of at least about 95-97% under accelerated conditions (40 ± 2 °C, 75 ± 5% relative humidity), and exhibit low turbidity (initial A600 values of about 0.0034-0.0099) (see Id., [0221]; [0227]; [0232]). By comparison, arginine-containing formulations described elsewhere in the application (for example, Examples 1-5) show initial turbidity values of about 0.0104-0.0147 and higher turbidity under thermal acceleration (see Id., [0l98]). As further described in the application as-filed, when the stabilizer in the pharmaceutical formulation of claim 31 is a mixture of threonine and methionine, the formulation generally exhibits lower turbidity values compared to formulations containing other stabilizers, including arginine. Turbidity is a commonly used indicator of physical stability in protein formulations. In Experimental Examples 4-2 and 4-3, formulations containing threonine/methionine mixtures in histidine buffer (Examples 17-22 and 23-27) have initial turbidity (A600) values in the range of about 0.0034-0.0099 and 0.0051-0.0086, respectively, whereas arginine-containing formulations described in Experimental Example 2 (Examples 1-5) exhibit initial turbidity values of about 0.0104-0.0147. Similar low initial turbidity values (about 0.0033-0.0082) are observed for additional threonine/methionine histidine formulations in Experimental Examples 4-4 and 4-5. In the art, high turbidity typically indicates the formation of protein aggregates and poorer physical stability, whereas low turbidity is indicative of better physical stability. Thus, the lower turbidity observed for the pharmaceutical formulation of claim 31 reflects an actual improvement in physical stability compared to arginine-stabilized formulations of the type taught by Bao.
In Liu, threonine appears only as one optional amino acid among a long list of potential excipients that may serve as bulking agents, solubility enhancers, stabilizers, or anti-denaturation agents, in addition to the specifically taught arginine-HCl/histidine/polysorbate systems. Liu does not teach using a stabilizer comprising an amino acid or amino acid derivative "wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine," and does not teach any embodiment in which arginine is removed and replaced with a threonine/methionine mixture as the stabilizer. Liu also does not teach any concentration for threonine, let alone the paired threonine and methionine concentration ranges recited in the instant claims as amended.
Bao and Liu teach arginine-based amino acid stabilizer systems and, at most, that additional amino acids such as threonine can be included somewhere in the formulation as optional excipients; the combined teachings do not provide any reason to replace Bao's arginine-based stabilizer with a stabilizer "comprising an amino acid or an amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine" as recited in claim 31, nor do they teach or suggest the specific paired threonine and methionine concentration ranges recited in claims 38 and 41.
In the absence of any teaching that threonine, in combination with methionine and without arginine, would yield acceptable-much less improved-stability, selecting the particular threonine/methionine stabilizer system and concentration ranges of claims 31, 38, and 41 from the broad and different excipient teachings in Bao and Liu would require impermissible hindsight reconstruction rather than a reasoned modification based on the prior art. Furthermore, Liu' s list of optional amino acids presents no teaching that any listed amino acid substitutes for the stabilizer actually taught by Liu-namely arginine-HCl used with histidine buffer and polysorbate. Threonine appears only as a non-preferential example in a long, undifferentiated list of optional excipients and is not paired with methionine in any embodiment.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to the arguments of improved physical stability of the instantly claimed formulation compared to arginine-based formulations, it is specifically noted that the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). It is noted that none of the data presented in the instant disclosure is identified as being statistically significant; thus absent statistical analysis it is not clear that the “improvement” argued by applicant is of both statistical and practical significance.
With regard to the arguments against Bao and Liu individually, it is noted that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981).
With regard to the arguments that Bao and Liu are directed to arginine-based amino acid stabilizer systems wherein at most, additional amino acids such as threonine can be included somewhere in the formulation as optional excipients such that the combined teachings do not provide any reason to replace Bao's arginine-based stabilizer with a stabilizer "comprising an amino acid or an amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine", it is specifically noted that the language of the instant claims is open claim language. With regard to the formulation itself, independent claim 31 (and notably dependent claims 40-41) recite “a stable pharmaceutical composition comprising” the recited surfactant, stabilizer, buffer, and antibody wherein the stabilizer is recited as “comprising an amino acid or amino acid derivative, wherein the amino acid or the amino acid derivative is a mixture of threonine and methionine” ; the recitation of “comprising”, in terms of the overall formulation and more specifically the stabilizer itself, does not exclude the presence of additional components. As such, while the preferred embodiments of Bao and Liu may be arginine-based, Liu explicitly indicates stable antibody formulations (having improved/optimized tonicity, turbidity, stability, solubility, etc.) may further comprise threonine and/or methionine (wherein an arginine/methionine mixture is explicitly suggested by Bao). Additionally, Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
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A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); < Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Thus, while preferred embodiments of Bao and Liu do include arginine, it is noted that Bao indicates that the “stabilizer” as defined may be a mixture of amino acids, and Liu specifically indicates that threonine in an acceptable amino acid stabilizer for use in high concentration, stable antibody formulations. As such, considering the identity and working concentrations of formulation components, including stabilizers, are recognized as result effective variable it would have been within the purview of one having ordinary skill in the art that different combinations of acceptable stabilizers may be utilized, wherein it would have been expected that the different combinations of the listed stabilizers would be expected to yield pharmaceutical formulations with similar properties.
With regard to arguments pertaining to predictability, it is noted that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Considering the compositions of Bao and Liu are both directed to high-concentration antibody formulations with improved/optimized properties (tonicity, turbidity, stability, solubility, etc.) and Liu indicates that additional carriers, excipients, and/or stabilizers (e.g., threonine) may be included, it would reasonably be expected that the addition of an additional carriers, excipients, and/or stabilizers would still yield a stable antibody formulation with similar properties.
With regard to the argument of impermissible hindsight, it is noted that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). The combination of Bao and Liu to render obvious the instantly claimed formulation relies solely on knowledge within the level of ordinary skill in the art at the time the claimed invention was made.
In view of the above, the new grounds of rejection regarding claims 31-35, 39-40, 42-44, and 46-47 being unpatentable in view of Bao and Liu is deemed proper, the rejection of claims 38, 41, and 45 as presented in the previous Office Action is deemed proper and is therefore maintained, and the above-listed claim rejections under nonstatuory double patenting are deemed proper and are therefore maintained.
Conclusion
Claims 31-35 and 38-47 are pending. Claims 31-35 and 38-47 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642