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 .
Election/Restrictions
Applicant’s election without traverse of species: (i) lysine as amino acid, (ii) sucrose as stabilizer, (iii) poloxamer as surfactant,(iv) CTLA4 as growth factor, (v) 9cps as kinetic viscosity, and (v) 800 mOsm/kg as Osmolality in the reply filed on 7/17/2026 is acknowledged.
Status of Application, Amendments, And/Or Claims
Claims 1-3, 6, 8, 12-18, 20,22-24, 26-27,29, 31-32, 34 and 36-40 are pending and under consideration to the extent they read on the elected species.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The instant applicant is 371 of PCT/IB2022/052377 filed on 3/16/2022.
Information Disclosure Statement
The Information Disclosure Statement filed on 7/17/2026 has been considered.
Specification
The disclosure is objected to because of the following informalities: the specification should be checked and corrected for the use of article throughout the specification, for example page 3, line 4: high concentration of …should start with “a high concentration of …”,
Page 3, line 5: suitable buffer…should start with “ a suitable buffer…
Page 3, line 6: suitable amino acid …should start with “ a suitable amino acid….”
Page 3, line 8: suitable stabilizer, should start with “ a suitable …”
Page 3, line 9: suitable surfactant, should start with “a suitable…”
Page 3, line 10: pH selected from, should be “a pH selected from….”
Applicants are suggested to check other errors throughout the specification.
Claim Objections
Claims 1, 14, 20,29, and 31 are objected to because of the following informalities: it is noted that syntax of claims 1, 29, 31 can be improved by inserting an article “a” before the term “pH selected from”
In claim 14, the examiner suggests inserting an article “a” before the term the term “sugar” in line 2.
In claim 20, the examiner suggests inserting an article “a” before the term the term “polysorbate” in line 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Regarding claim 1, the phrase "suitable amino acids" renders the claim indefinite because it is unclear whether a suitable amino acid is a neutral amino acid, a lipophilic amino acid, a basic amino acid, an acidic amino acid, a hydrophilic amino acid or something like a synthetic non-natural amino acid. Therefore, the metes and bounds of the claim cannot be determined. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112
Claims 1-3, 6, 8, 12-18, 20,22-24, 26-27,29, 31-32, 34 and 36-40 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.
The written description in this case only sets forth for a pharmaceutical liquid formulation comprising fusion protein CTLA-4 IgG1 fusion 125 mg/ml, L-lysine HCl 150 mM, Poloxamer 188 at 8 mg/mL, sucrose 110/g/L having a pH of about 6.5 to about 7.5, viscosity of about 9 cPs and osmolality about 800 mOsm/kg, and therefore the written description is not commensurate in scope with “a liquid formulation comprising a high concentration of any physiologically active fusion protein, any suitable amino acid, any stabilizer and any surfactant that results in a pH of about 6.5 to about 7.5”.
The claims broadly encompasses any liquid formulation comprising any pharmacologically active fusion protein, having any suitable amino acid, any stabilizer, a histidine buffer that results in a pH selected from about pH 6.5-7.5 and has osmolality of about 700-900 mOsm/kg.
The specification at pg. 33, Example 7 discloses a liquid formulation having a fusion protein CTLA-4 IgG1 at 125 mg/ml, L-Histidine (150 mM), sucrose, L-lysine, Poloxamer188 about 8 mg/mL that has low amount aggregate of high mol. weight (HMW) species by SEC at day 14 of about 0.88, and day 28 of about 1.7; and LMW at day 14 about 0.85 and at day 28 about 1.46. The specification discloses use of phosphate buffer and L-arginine (example 6) that resulted in higher percentage of HMW and LMW at day 14 and day 28. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. Some of the factual considerations that are weighed when determining a written description include the level of skill and knowledge in the art, the disclosure of complete or partial structures, the disclosure of physical and or chemical properties, adequate disclosure of the functional characteristics, the correlation between structure and function, and disclosure of methods of making.
WO 2009058564 teaches making a liquid composition of CTLA-4-Ig fusion. Choi et al. (CA 2837176) teaches making fusion proteins comprising an amino acid and stabilizer.
The specification at pg. 33, Example 7 discloses a liquid formulation having a fusion protein CTLA-4 IgG1 at 125 mg/ml, L-Histidine (150 mM), sucrose, L-lysine, Poloxamer188 about 8 mg/mL. The specification does not disclose sufficient representative of the genus “any pharmacologically active fusion protein” that comprises a genus of “any suitable amino acid”, “any stabilizer” and “any surfactant”. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1 "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states an adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.
As discussed above, the skilled artisan cannot envision the detailed genus of “a liquid formulation comprising any physiologically active fusion protein, any suitable amino acid, any stabilizer and any surfactant that results in a pH of about 6.5 to about 7.5” and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of making a mutation. The compound itself is required. See Fiers v.Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen v.Baird, 30 Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 148 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class.
Therefore, only a liquid formulation comprising fusion protein CTLA-4 IgG1 fusion 125 mg/ml, L-lysine HCl 150 mM, Poloxamer 188 at 8 mg/mL, sucrose 110/g/L having a pH of about 6.5 to about 7.5, viscosity of about 9 cPs and osmolality about 800 mOsm/kg, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-3, 6, 8, 12-18, 20,22-24, 26-27,29, 31-32, 34 and 36-40 are rejected under 35 U.S.C. 103 as being unpatentable over Karrer et al. (WO 2009058564) in view of Shenoy (IDS, US 20180333493), Choi et al. (AU 2012263100) and Fernandez et al. (US 20100137213).
The instant invention is broadly drawn to a pharmaceutical formulation comprising a pharmacologically active fusion protein, a histidine buffer, a suitable amino acid, a stabilizer, a surfactant and a pH selected from about 6.6-7.5 (claim 1, 29-30), wherein the fusion protein is about 125 mg/ml (claim 2-3), wherein the histidine buffer is from about 100 mM-200 mM (claim 6), wherein the suitable amino acid is from about 10 mM to 200 mM and wherein the suitable amino acid is Arg, Lys, Gly Pro or a suitable salt thereof (claim 8, 12, 13), wherein the stabilizer is sugar or cyclodextrin (claim 14), wherein the concentration of sugar is lower than the concentration of the fusion protein (claim 15, 17), wherein the sugar is sucrose (claim 16), wherein the concentration of sucrose is from about 110 mg /ml to 120 mg/ml (claim 18), wherein the surfactant is polysorbate or poloxamer 188 (claim 20), wherein the surfactant is poloxamer at a concentration of about 1 mg/mL-10 mg/mL (claim 22-23), wherein the pH of the liquid formulation is from about 6.8-7.4 (claim 24), wherein the fusion protein is CTLA4-Ig (claim 26-27), a drug delivery device comprising the formulation of claim 1 (claim 32). The formulation of claim 1, wherein the kinetic viscosity of the formulation is about cPs to about 15 cPs (claim 34), wherein the osmolality of formulation is about 700 mOsm/kg, to about 900 mOsm/kg (claim 36), 37. (Currently Amended) The pharmaceutical liquid formulation according to claim 1,wherein the pharmaceutical liquid formulation comprises reduced amount of low molecular weight (LMW) impurities compared to pharmacologically active fusion protein formulated with phosphate buffer (claim 37). The pharmaceutical liquid formulation according to claim 1, wherein the pharmaceutical liquid formulation is essentially free of histidine amino acid. The pharmaceutical liquid formulation according to claim 1, wherein the pharmaceutical liquid formulation comprises reduced amount of high molecular weight (HMW) impurities compared to the pharmacologically active fusion protein formulated with phosphate buffer. The pharmaceutical liquid formulation according to claim 1, wherein the pharmaceutical liquid formulation comprises LMW below 10% and wherein high molecular weight (HMW) impurities in an amount below 10%.
Regarding claims 1-3, Karrer et al. teaches a fusion protein wherein the fusion protein is a soluble CTLA-4-Ig (see pg. 2) and the pH of formulation is 6.5 to about 7.4 (pg. 192). They teach the formulation in a phosphate buffer which comprises a sugar such as sucrose (pg.192). But they teach that the buffer can be histidine buffer (see pg. 222, line 17). They teach that the formulation is suitable for parenteral administration (subcutaneously, intravenously, intramuscularly, etc.,) (pg. 193, ines8+). They teach that the concentration of the fusion protein is form 0.1 mg to 200 mg/ml (pg.193, lines 12+). Kerrer et al. do not teach a liquid formulation of a fusion protein that comprises a suitable amino acid, or surfactant.
Shenoy discloses low-viscosity, high concentration therapeutic protein agent formulations that allow for stable long-term storage, comprising 150 to 300 mg/mL of a therapeutic protein agent that is a monoclonal antibody or fragment thereof, 15 to 25 mM of a phosphate or L-histidine buffer, 50 to 200 mM of one or more viscosity reducing agents such as arginine or lysine, and one or more excipients including surfactants such as polysorbate 20, polysorbate 80, or poloxamer 188
added in the range of 0.001% to 1.0% (w/v) (or. 0.001 to 5.0%) (abstract, summary of invention, paragraph [0007-0011, 0036-0039, 0049, 0111, 0152]. Shenoy teaches viscosity reducing agents [0210, 0218]. The buffer can also be present from
about 10-300 mM (Claim 17), which would encompass 5-20 mg/mL histidine, equivalent to about 40 to 160 mM. Salts of amino acids including lysine or arginine are also contemplated (Para. 0258). A stable formulation can be one in which more than 95% of the bioactive protein molecules retain bioactivity in a formulation after 1 month of storage at 40°C (Para. 0162). The use of a viscosity-reducing agent reduces the viscosity of the protein agent formulation to a viscosity in the range of about 5 cP to 15 cP when measured at 25°C ([0054 and 0168]). The pH can be adjusted to maximize stability and solubility of a particular protein agent and, in some embodiments, can be in the range of about 6.2 to 7.0 (Para. 0055).
Choi et al. teach making a stable liquid formulation of etanercept (sTNFR-Fc fusion protein) comprising a stabilizer selected from lysine, methionine, and a pharmaceutically acceptable salt thereof to reduce by-product during storage (see abstract). They teach to use surfactant polysorbate about 0.02-0.04% (see page 2, [5]). They teach that 10-200 mM of L-arginine can be used as aggregation preventing agent (pg. 3 [11]). They teach to add sucrose as an isotonic agent (see pg.4 [25]). Regarding claims 8, 12-13, they teach to include lysine in an amount 0.1 to 250 mM (see pg. 4 [21], pg. 5 [31])). They used HI-HPLC to analyze the purity of formulation and to determine stabilization by lysine or methionine (pg. 6, [39]). Regarding claim 20, they teach use of polysorbate or poloxamer 188 in the formulation (pg. 13 [86]). Regarding claim 32, they teach to use a device as 1 mL glass syringe comprising the formulation to store at 50 °C (pg. 13 [87]).
Regarding claims34, 36-37, 39-40, Fernandez et al. teach analyzing high concentration containing liquid formulation for Low molecular weight aggregate (LMW) and HMW by HPLC (Fig. 17, Figure 20). They teach many devices for drug delivery [208]. They teach measuring viscosity of a formulation [220]. They teach that HMW species after six months storage at 4 °C and 25 °C is about 0.1-0.2% (see [0227]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to determine the effect of stabilizer and surfactant for the presence of HMW and LMW as taught by Fernandez for the presence of surfactant poloxamer188, amino acid lysine using HPLC as taught by Choi et al. and to adjust pH in histidine buffer, viscosity adjustment as taught by Shenoy in a high concentration liquid formulation of CTLA-4-Ig fusion protein as taught by Kerrer et al. Additionally, one would have been motivated to do so because Choi et al teach to make a stable liquid formulation of a fusion protein and Fernandez et al teach determining LMW and HMW aggregates at different temperature for different storage condition and that would provide a suitable high quality liquid formulation for CTLA-4 Ig fusion protein. Further, one would have a reasonable expectation of success in using a suitable amino acid like lysine, surfactant such as polysorbate or poloxamer 188 as taught by Choi et al and to determine the stability of liquid formulation using HPLC for the presence of a HMW and LMW aggregates as taught by Fernandez and to have sufficient viscosity by adjusting agents taught by Shenoy in a liquid formulation comprising CTLA-4-Ig fusion protein. Therefore, the instantly claimed invention would have been obvious over the combined teachings of the prior art.
Generally, differences in concentrations of components of a formulation do not support the patentability of subject matter encompassed by the prior art. Such formulations are results-effective variables which can be optimized. In in re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980), it was held that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As formulating optimal compositions for medicaments is routine in the art of pharmacology, the claims are considered to be prima facie obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GYAN CHANDRA whose telephone number is (571)272-2922. The examiner can normally be reached Mon-Friday 8:30AM-5:00P.
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/GYAN CHANDRA/Primary Examiner, Art Unit 1674
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