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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
Claims 1-10 are pending. Claims 1-10 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statement filed on 11/26/22 has been considered. A signed copy is enclosed.
Applicant is advised that the listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in a Search Report will not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they will be considered.
Claim Objections
Claim 1 is objected to because of the following informalities: the phrase “has pH” should be amended to read “has a pH”. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: the phrase “has osmolality about” should be amended to read “has an osmolality of about”. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: the phrase “wherein pH” should be amended to read “wherein the pH”. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the phrase “is free of buffer system selected from group” should be amended to read “is free of a buffer system selected from the group”. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: the phrase “wherein the composition is free stabilizers” should be amended to read “wherein the composition is free of stabilizers”. Appropriate correction is required.
Claim 8 is objected to because of the following informalities: the phrase “has osmolality about” should be amended to read “has an osmolality of about”. Appropriate correction is required.
Claim 9 is objected to because of the following informalities: the phrase “wherein pH” should be amended to read “wherein the pH”. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: the phrase “is free of buffer system selected from group” should be amended to read “is free of a buffer system selected from the group”. Appropriate correction is required.
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--10 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, 4, 5, 7, and 10 recite the phrase “free of stabilizers selected from the group consisting of” or “free of buffer system selected from the group consisting of”. The phrase renders the claims indefinite. It is unclear if the limitation requires that the composition is free of all of the stabilizers or buffers that are encompassed within the Markush group, or if the limitation only requires that the composition is free of at least one of the recited Markush group. Therefore the scope of the encompassed stabilizers and buffers is indefinite.
Claims 1-3 and 5-9 recite the term “about”. There is nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of concentrations is covered by the term "about." See MPEP 2173.05(b).
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Claim Interpretation
Claims 1, 4, 5, 7, and 10 recite the phrase “free of stabilizers selected from the group consisting of” or “free of buffer system selected from the group consisting of”. It is unclear if the limitations require that the composition is free of all of the stabilizers or buffers that are encompassed within the Markush group, or if the limitation only requires that the composition is free of at least one of the recited Markush group. For the purposes of examination, this phrase will be given the broadest reasonable interpretation, which requires that the formulation is free of at least one of the encompassed stabilizers or buffer systems, but is not required to be free of all of the encompassed stabilizers or buffer systems.
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, 3-5, 7, 9-10 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Antochshuk et al (US 9,844,594 B2; filed 12/13/13; published 12/19/17.
The instant claims are directed to a stable aqueous pharmaceutical composition comprising (a) about 25 mg/mL to about 200 mg/mL adalimumab, (b) about 5 mg/mL to about 35 mg/mL mannitol, (c) about 0.1 mg/mL to about 10 mg/mL polysorbate 80, and (d) a buffer system consisting of succinate, wherein the composition has pH of about 4.5 to about 6.5 and wherein the composition is free of stabilizers selected from group consisting of sodium chloride and amino acids. The composition may have an osmolality of about 180 mOsM/kg to about 400 mOsM/kg. The pH may be about 5.2. The composition may be free of buffer system selected from group consisting of citrate, phosphate, histidine, tartrate, acetate and maleate. The claims are also drawn to a stable aqueous pharmaceutical composition consisting of (a) about 25 mg/mL to about 200 mg/mL adalimumab, (b) about 5 mg/mL to about 35 mg/mL mannitol, (c) about 0.1 mg/mL to about 10 mg/mL polysorbate 80, and (d) a buffer system consisting of succinate, wherein the composition has a pH of about 4.5 to about 6.5 and wherein the composition is free of stabilizers selected from group consisting of sodium chloride and amino acids. The claims are also directed to a stable aqueous composition as claimed in claim 5 consisting of (a) about 100 mg/mL adalimumab, (b) about 35 mg/mL mannitol, (c) about 1 mg/mL polysorbate 80 and (d) a buffer system consisting of succinate, wherein the composition has a pH of about 4.5 to about 6.5. The claims are also directed to a stable aqueous pharmaceutical composition comprising (a) about 25 mg/mL to about 200 mg/mL adalimumab, (b) about 5 mg/mL to about 50 mg/mL mannitol, (c) about 0.1 mg/mL to about 10 mg/mL polysorbate 80 and (d) a buffer system consisting of citrate, wherein the composition has a pH of about 4.5 to about 6.5 and wherein the composition is free stabilizers selected from group consisting of sodium chloride and amino acids. The composition can have an osmolality of about 180 mOsM/kg to about 400 mOsM/kg. The composition can have a pH of about 5.2. The composition can be free of buffer system selected from group consisting of succinate, phosphate, histidine, tartrate, acetate and maleate.
Regarding the limitations of instant claim 1 and 5, Antochshuk teaches formulations that have 50 mg/mL antibody, 10 mM succinate buffer system, 1.2% mannitol, 0.1% polysorbate 80, and NaCl at 105 mM (see e.g. Table 3, column 27). An example stable aqueous liquid formulation comprises adalimumab, 0.5 mg/ml succinic acid (as the buffering component), 5.17 mg/ml sodium chloride, 19.50 mg/ml mannitol, and 1.0 mg/ml Polysorbate 80, and water, with a pH of 5.3 (see e.g. claim 4). Another example is formula 13 in Table 6, which contains 50 mg/ml of adalimumab (see column 30 lines 12-16), 5.165 mg/mL NaCl, 19.5 mg/ml mannitol, 1 mg/ml polysorbate 80, 0.48 mg/ml succinic acid, at a pH of 5.3. The formulation does not contain any amino acids, and therefore meets the limitation of the instant claims requiring that the composition “is free of stabilizers selected from the group consisting of sodium chloride and amino acids”. Regarding instant claim 5, the language indicates that stabilizers may be present, as long as not all of the stabilizers listed in the Markush group are present. The formulation of Antochshuk meets these limitations.
Regarding the limitations of instant claim 3, Antochshuk teaches formulations that have a pH of 5.3 (see e.g. claim 4). The instant claim is directed to “about 5.2” for pH. However, the instant specification does not define the term “about”. Given that 5.3 is less than 2% different from 5.2, the pH of Antochshuk would reasonably fall within the range described as “about 5.2”.
Regarding instant claim 4, the language indicates that buffers selected from the group consisting of citrate, phosphate, histidine, tartrate, acetate, and maleate may be present, as long as not all of the buffers listed in the Markush group are present. The formulation of Antochshuk meets these limitations by not comprising at least tartrate, acetate, and maleate.
Regarding the limitations of instant claim 7, Table 1 of Antochshuk teaches the commercial formulation of HUMIRA, which has 40 mg/0.8mL or 50 mg/ml antibody, a buffer system comprising sodium citrate and citric acid monohydrate, 9.9 mg/0.8 mL or about 12 mg/ml mannitol, 0.8 mg/0.8 ml or 1 mg/mL polysorbate 80, and NaCl at 4.93 mg/0.8 mL (see e.g. Table 1, column 12). The formulation does not contain any amino acids, and therefore meets the limitation of the instant claims requiring that the composition “is free of stabilizers selected from the group consisting of sodium chloride and amino acids”.
Regarding the limitations of instant claim 9, Antochshuk teaches that the HUMIRA formulation comprises a pH of about 5.2 (see e.g. column 12, lines 34-35).
Regarding instant claim 10, the language indicates that buffers selected from the group consisting of citrate, phosphate, histidine, tartrate, acetate, and maleate may be present, as long as not all of the buffers listed in the Markush group are present. The formulation of Antochshuk meets these limitations by not comprising at least tartrate, acetate, and maleate.
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(s) 1-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Antochshuk et al (US 9,844,594 B2; filed 12/13/13; published 12/19/17.
The instant claims are directed to a stable aqueous pharmaceutical composition comprising (a) about 25 mg/mL to about 200 mg/mL adalimumab, (b) about 5 mg/mL to about 35 mg/mL mannitol, (c) about 0.1 mg/mL to about 10 mg/mL polysorbate 80, and (d) a buffer system consisting of succinate, wherein the composition has pH of about 4.5 to about 6.5 and wherein the composition is free of stabilizers selected from group consisting of sodium chloride and amino acids. The composition may have an osmolality of about 180 mOsM/kg to about 400 mOsM/kg. The pH may be about 5.2. The composition may be free of buffer system selected from group consisting of citrate, phosphate, histidine, tartrate, acetate and maleate. The claims are also drawn to a stable aqueous pharmaceutical composition consisting of (a) about 25 mg/mL to about 200 mg/mL adalimumab, (b) about 5 mg/mL to about 35 mg/mL mannitol, (c) about 0.1 mg/mL to about 10 mg/mL polysorbate 80, and (d) a buffer system consisting of succinate, wherein the composition has a pH of about 4.5 to about 6.5 and wherein the composition is free of stabilizers selected from group consisting of sodium chloride and amino acids. The claims are also directed to a stable aqueous composition as claimed in claim 5 consisting of (a) about 100 mg/mL adalimumab, (b) about 35 mg/mL mannitol, (c) about 1 mg/mL polysorbate 80 and (d) a buffer system consisting of succinate, wherein the composition has a pH of about 4.5 to about 6.5. The claims are also directed to a stable aqueous pharmaceutical composition comprising (a) about 25 mg/mL to about 200 mg/mL adalimumab, (b) about 5 mg/mL to about 50 mg/mL mannitol, (c) about 0.1 mg/mL to about 10 mg/mL polysorbate 80 and (d) a buffer system consisting of citrate, wherein the composition has a pH of about 4.5 to about 6.5 and wherein the composition is free stabilizers selected from group consisting of sodium chloride and amino acids. The composition can have an osmolality of about 180 mOsM/kg to about 400 mOsM/kg. The composition can have a pH of about 5.2. The composition can be free of buffer system selected from group consisting of succinate, phosphate, histidine, tartrate, acetate and maleate.
Regarding the limitations of instant claim 1 and 5, Antochshuk teaches formulations that have 50 mg/mL antibody, 10 mM succinate buffer system, 1.2% mannitol, 0.1% polysorbate 80, and NaCl at 105 mM (see e.g. Table 3, column 27). An example stable aqueous liquid formulation comprises adalimumab, 0.5 mg/ml succinic acid (as the buffering component), 5.17 mg/ml sodium chloride, 19.50 mg/ml mannitol, and 1.0 mg/ml Polysorbate 80, and water, with a pH of 5.3 (see e.g. claim 4). Another example is formula 13 in Table 6, which contains 50 mg/ml of adalimumab (see column 30 lines 12-16), 5.165 mg/mL NaCl, 19.5 mg/ml mannitol, 1 mg/ml polysorbate 80, 0.48 mg/ml succinic acid, at a pH of 5.3. The formulation does not contain any amino acids, and therefore meets the limitation of the instant claims requiring that the composition “is free of stabilizers selected from the group consisting of sodium chloride and amino acids”. Regarding instant claim 5, the language indicates that stabilizers may be present, as long as not all of the stabilizers listed in the Markush group are present. The formulation of Antochshuk meets these limitations.
Regarding the limitations of instant claim 3, Antochshuk teaches formulations that have a pH of 5.3 (see e.g. claim 4). The instant claim is directed to “about 5.2” for pH. However, the instant specification does not define the term “about”. Given that 5.3 is less than 2% different from 5.2, the pH of Antochshuk would reasonably fall within the range described as “about 5.2”.
Regarding instant claim 4, the language indicates that buffers selected from the group consisting of citrate, phosphate, histidine, tartrate, acetate, and maleate may be present, as long as not all of the buffers listed in the Markush group are present. The formulation of Antochshuk meets these limitations by not comprising at least tartrate, acetate, and maleate.
Regarding the limitations of instant claim 7, Table 1 of Antochshuk teaches the commercial formulation of HUMIRA, which has 40 mg/0.8mL or 50 mg/ml antibody, a buffer system comprising sodium citrate and citric acid monohydrate, 9.9 mg/0.8 mL or about 12 mg/ml mannitol, 0.8 mg/0.8 ml or 1 mg/mL polysorbate 80, and NaCl at 4.93 mg/0.8 mL (see e.g. Table 1, column 12). The formulation does not contain any amino acids, and therefore meets the limitation of the instant claims requiring that the composition “is free of stabilizers selected from the group consisting of sodium chloride and amino acids”.
Regarding the limitations of instant claim 9, Antochshuk teaches that the HUMIRA formulation comprises a pH of about 5.2 (see e.g. column 12, lines 34-35).
Regarding instant claim 10, the language indicates that buffers selected from the group consisting of citrate, phosphate, histidine, tartrate, acetate, and maleate may be present, as long as not all of the buffers listed in the Markush group are present. The formulation of Antochshuk meets these limitations by not comprising at least tartrate, acetate, and maleate.
Antochshuk does not teach the osmolality range of instant claims 2 and 8, or the specific formulation of instant claim 6.
However, Antochshuk recognizes that “Various modifications of the invention in addition to those suitable for human or animal administration , or to facilitate shown and described herein will become apparent to those skilled in the art” (see Antochshuk, column 26, lines 1-12). Additionally, the instant specification recognizes that “While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.” (see e.g. paragraph [0068] of the instant specification).
Therefore, it would have been obvious to one of skill in the art to optimize the formulations of Antochshuk to arrive at the instant claimed formulations. Based on the above established facts from the cited prior art, it appears that all of the instant claimed elements (i.e., individual components in the composition and a range of concentrations that encompasses all concentrations named in the instant claims) were known in the prior art, and one skilled in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results. Furthermore, the concentrations of the reference overlaps for components with the instant claimed ranges. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of components in the composition, since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
For all of these reasons, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and engage in routine optimization to arrive at the instantly claimed composition with a reasonable expectation of success. The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their commonly known purpose. See MPEP 2144.07.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674