DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 2, 5-29 and 33-35 are pending.
Claims 11-20, 28 and 29 have been withdrawn.
Claims 1, 2, 5-10, 21-27 and 33-35 are currently under examination.
35 USC § 112(b) rejections withdrawn
The rejection of claims 1, 2, 5-10 and 21-27, as being indefinite for failing to particularly point out and distinctly claim the subject matter are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 102 rejections withdrawn
The rejection of claims 1, 6-9, 21-23 and 25-27 under 102(a1)(a2) as being anticipated by Dave et al (US 2013/0058930, March 7, 2013, IDS) are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 103 rejections withdrawn
The rejections of claim(s) 1, 2, 5-10, 21-26 under 35 U.S.C. 103 as being unpatentable over Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) in view of Lazar et al (2017/0252437, published September 7, 2017, IDS) are withdrawn in view of Applicant’s amendments to claim 1.
The rejections of claim(s) 1, 2, 5-10, 21-27 under 35 U.S.C. 103 as being unpatentable over Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) in view of Lazar et al (2017/0252437, published September 7, 2017, IDS, cited previously) in further view of Murphy et al (US 2020/0164087, published May 28, 2020, IDS) are withdrawn in view of Applicant’s amendments to claim 1.
The rejections of claim(s) 1, 5-10 and 21-26 under 35 U.S.C. 103 as being unpatentable over Jones et al (US 2023/0312700, published October 5, 2023, effective filing date June 19, 2019) are withdrawn in view of Applicant’s amendments to claim 1.
The rejections of claims 1, 2, 5-10 and 21-26 under 35 U.S.C. 103 as being unpatentable over Jones et al (US 2023/0312700, published October 5, 2023, effective filing date June 19, 2019, cited previously) in view of Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) and Meyers et al (US 2021/0213201, published July 15, 2021, effective filing date August 7, 2020) are withdrawn in view of Applicant’s amendments to claim 1.
The rejections of claims 1, 2, 5-10 and 21-27 under 35 U.S.C. 103 as being unpatentable over Jones et al (US 2023/0312700, published October 5, 2023, effective filing date June 19, 2019, cited previously) in view of Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) and Meyers et al (US 2021/0213201, published July 15, 2021, effective filing date August 7, 2020, cited previously) in further view of Murphy et al (US 2020/0164087, published May 28, 2020, IDS, cited previously) are withdrawn in view of Applicant’s amendments to claim 1.
NEW REJECTIONS: Based on the Amendment
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.
Claim 35 is 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.
Claim 35 recites a pharmaceutical composition comprising methotrexate or a pharmaceutically acceptable salt, hydrate or derivative thereof. Claim 35 is indefinite for reciting “derivative” because the exact meaning of the term is not clear. The term “derivative” is not one, which has a universally accepted meaning in the art nor is it one which has been adequately defined in the specification. The primary deficiency in the use of this phrase is the absence of an ascertainable meaning for said phrase. Since it is unclear how the methotrexate is derivatized to yield the class of methotrexate derivatives referred to in the claims, there is no way for a person of skill in the art to ascribe a discrete and identifiable class of compounds to said phrase. In addition, since the term “derivative” does not appear to be clearly defined in the specification, and the term can encompass many compounds which are only slightly related to methotrexate. In the absence of a single defined art recognized meaning for the phrase and lacking a definition of the term “derivative” in the specification, one of skill in the art could not determine the metes and bounds of the claims.
Claim Rejections - 35 USC § 102
(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.
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) 35 is/are rejected under 35 U.S.C. 102(a1)(a2) as being anticipated by Dave et al (US 2013/0058930, March 7, 2013, IDS).
The claims are drawn to a pharmaceutical composition comprising methotrexate or a pharmaceutically acceptable salt, hydrate or derivative thereof, and at least one pharmaceutically active biopharmaceutical which is at least partially dissolved in the solvent in combination with the methotrexate or the pharmaceutically acceptable salt, hydrate or derivative thereof.
Dave disclose a pharmaceutical composition comprising a combination of methotrexate and infliximab (paragraph 76). Dave disclose injectable solutions comprising 20 mg methotrexate per 0.4 ml (50 mg/ml) (paragraphs 120, 121). Dave disclose an injection device for subcutaneous or intramuscular administration of a medicament comprising methotrexate (paragraphs 74-87). Dave discloses methods of treating autoimmune and inflammatory disorders, including rheumatoid arthritis, with methotrexate and infliximab (paragraphs 2, 11-15, 76, claim 25).
Relevant arguments pertaining to Dave
Applicant argues that Dave does not disclose that methotrexate and the biological agent are both present in the same solution. Applicant argues that in [0076] of Dave it does not even disclose that methotrexate and the other active ingredient are administered using the same jet injector, i.e., simultaneously. Applicant argues that [0076] cannot and does not disclose that methotrexate and a biological agent are at least partially dissolved together in one and the same solution. Applicant argues that the disclosure of Dave refers to a conventional combination therapy of methotrexate and a biological agent. Applicant argues that solutions of methotrexate are disclosed elsewhere in Dave, but not in connection with joint administration with a biological agent. Applicant argues that [0120]-[0121] of Dave are disclosed injectable solutions of methotrexate which have no connection whatsoever to the biological agent.
In addition, Applicant argues that the disclosure and teaching of Dave refer explicitly and exclusively to the administration of active substances by means of jet injectors. Applicant argues that a solvent in which the biological agent is dissolved, let alone in which methotrexate and the biological agent are dissolved together as required by present claim 1, is therefore also not inherently required by the disclosure of Dave.
Applicant’s arguments have been considered but are not persuasive. A prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123. In this case, Dave discloses provides a method of treating an autoimmune disorder in a subject in need of treatment, comprising introducing into the subcutaneous tissue of the subject, from a needle assisted jet injection device, a composition comprising a combination of methotrexate with one or more therapeutic agents, including infliximab (paragraph 76). Thus, Dave does disclose a solvent in which the biological agent is dissolved together as required by present claim 1. It is not clear how a composition comprising a combination of methotrexate and infliximab would not be dissolved together. Dave clearly discloses a composition comprising a combination of methotrexate and infliximab. It appears as if Applicant is arguing that the method for preparing a composition comprising a combination of methotrexate and infliximab is distinct from the method of preparing as laid out in Dave. However, the claims are drawn to a composition not a method of preparing the composition.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 2, 5-10, 21-26 and 33-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) in view of Lazar et al (2017/0252437, published September 7, 2017, IDS) in further view of Boldajipour et al (US 2023/0192839, published June 22, 2023, filing date March 29, 2018) and Hochberg et al (Ann Rheum Dis 62(Suppl II):ii13-ii16, 2003).
Dave disclose a pharmaceutical composition comprising a combination of methotrexate and infliximab (paragraph 76). Dave disclose injectable solutions comprising 20 mg methotrexate per 0.4 ml (50 mg/ml) (paragraphs 120, 121). Dave disclose an injection device for subcutaneous or intramuscular administration of a medicament comprising methotrexate (paragraphs 74-87). Dave discloses methods of treating autoimmune and inflammatory disorders, including rheumatoid arthritis, with methotrexate and infliximab (paragraphs 2, 11-15, 76, claim 25).
Dave does not disclose that the biopharmaceutical is adalimumab.
Lazar discloses pharmaceutical compositions of adalimumab at 1-150 mg/ml (paragraph 25). Lazar disclose that the pharmaceutical adalimumab formulation is designed for subcutaneous administration for use in the treatment of an autoimmune
Disorder, including rheumatoid arthritis (paragraphs 26, 144).
One of ordinary skill in the art would have been motivated to apply Lazar’s biopharmaceutical, adalimumab with Dave’s pharmaceutical composition comprising methotrexate because both adalimumab and methotrexate are used to treat autoimmune and inflammatory disorders. The court has held that it is obvious to combine two compositions, in order to form a third composition, when each of the two compositions is taught by the prior art to be useful for the same purpose. (In re Kerkhoven, 626, F.2s 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine Dave’s pharmaceutical composition comprising methotrexate with Lazar’s biopharmaceutical, adalimumab because the prior art teaches that both are useful for the treatment of autoimmune and inflammatory disorders. It would have been prima facie obvious to substitute Lazar’s biopharmaceutical, adalimumab for Dave’s pharmaceutical composition comprising infliximab because both infliximab and adalimumab are anti-TNF antibodies that have been shown to treat autoimmune and inflammatory disorders.
With regards to the limitations wherein the at least one pharmaceutically active biopharmaceutical and the methotrexate are present in a mass ratio of 10:1 to 1:10, 6:1 60 1:3 or 3:1 to 1:1. in the composition, Dave disclose injectable solutions comprising 20 mg methotrexate per 0.4 ml (50 mg/ml) while Lazar discloses pharmaceutical compositions of adalimumab at 1-150 mg/ml. Thus, the claimed mass ratios are encompassed by the amounts of adalimumab and methotrexate in Lazar and Dave, respectively. In addition, Hochberg discloses Weinblatt added adalimumab at a dose of 20, 40, or 80 mg every other week by subcutaneous injection to 271 patients with RA who had been receiving methotrexate at their maximal tolerated dose of between 12.5 and 25 mg/week (ii14, 2nd column). Hochberg disclose Keystone added adalimumab at a dose of 20 mg weekly to 619 patients with RA who had been receiving methotrexate at their maximal tolerated dose (Id). Thus, Houchberg discloses mass ratios of methotrexate (12.5 – 25 and adalimumab that fall within the claimed mass ratios of the biopharmaceutical and methotrexate.
Furthermore, the limitations the pharmaceutically active biopharmaceutical and the methotrexate are present in a mass ratio of 10:1 to 1:10, 6:1 60 1:3 or 3:1 to 1:1. in the composition, the mass ratio of the composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "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."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); 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).
Neither Dave nor Lazar disclose that the derivative of methotrexate has a structure of methotrexate but with a different atom or functional group in place of a hydrogen atom.
Boldajipour disclose a methotrexate that has been pegylated to improve the properties of the methotrexate. (paragraph 96).
One of ordinary skill in the art would have motivated to apply Boldajipour’s disclosure of a modified methotrexate to Dave and Lazar’s composition comprising adalimumab and methotrexate because Boldajipour discloses that pegylation of methotrexate improves the properties of methotrexate. It would have been prima facie obvious to combine Dave and Lazar’s composition comprising adalimumab and methotrexate with Boldajipour’s disclosure of a modified methotrexate to have a pharmaceutical composition comprising methotrexate and adalimumab wherein adalimumab and methotrexate are present in a mass ratio of 10:1 to 1:10 in the composition: and wherein the derivative has a structure of methotrexate but with a different atom or functional group in place of a hydrogen atom.
Claim(s) 1, 2, 5-10, 21-27 and 33-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) in view of Lazar et al (2017/0252437, published September 7, 2017, IDS, cited previously), Boldajipour et al (US 2023/0192839, published June 22, 2023, filing date March 29, 2018) and Hochberg et al (Ann Rheum Dis 62(Suppl II):ii13-ii16, 2003) in further view of Murphy et al (US 2020/0164087, published May 28, 2020, IDS).
Neither Dave, Lazar, Boldajipour nor Hochberg disclose a drug-loaded nanoparticle or microparticle comprising the pharmaceutical composition comprising methotrexate and an active pharmaceutical.
Murphy disclose mineral coated microparticles for sustained delivery of biologically active molecules (paragraphs 9-14). Murphy discloses that suitable biologically active molecules include adalimumab and infliximab (paragraph 111).
One of ordinary skill in the art would have been motivated to apply Murphy’s mineral coated microparticles to Dave, Lazar, Boldajipour and Hochberg ’s pharmaceutical composition comprising methotrexate and adalimumab because Murphy discloses suitable active agents include infliximab, adalimumab and methotrexate (paragraphs 9-16, 51, 87) and recites that the microparticle would provide sustained delivery and/or local delivery of biologically active molecules and could be used to treat autoimmune and inflammatory disease (Id). It would have been prima facie obvious to combine Dave, Lazar, Boldajipour and Hochberg ’s pharmaceutical composition comprising methotrexate and adalimumab with Murphy’s mineral coated microparticles comprising adalimumab and methotrexate to have a drug-loaded microparticle comprising methotrexate and adalimumab.
Relevant arguments concerning unexpected results
Applicant argues that advantageous interaction occurs between MTX (methotrexate, a first-line antirheumatic drug) and the biopharmaceutical Applicant argues that this was attributed to MTX dissolving and increasing the solubility, stability, and binding affinity of the biologic. Applicant argues that a combination of both substances resulted in an improved dose response relationship in the composition. Applicant argues that the amounts resulting in the at least partial dissolution are not disclosed in Dave, neither would one of ordinary skill have predicted an improvement in bioactivity as shown in the present application. Applicant argues that the claimed ratios results in the increased binding strengths of the biopharmaceutical (between 5-132 (% ), compared to reference compositions without MTX.
Applicant’s arguments have been considered but are not persuasive. As an initial matter, MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
The results of Figure 2 and the table on page 35 discloses that adalimumab, etanercept, abatacept, infliximab and golimumab had different denaturation temperatures and relative increases in binding strength in the presence of methotrexate. Thus, the unexpected results described by Applicants are not commensurate in scope with the breadth of the claims as currently presented. The claims recite a composition comprising any biopharmaceutical composition. However, the specification only discloses the improvement of a couple of properties of five antibodies in the presence of methotrexate.
It is noted that methotrexate only increases the relative binding strength of adalimumab to TNF from 147.3 pm to 139.7 pm with no standard deviations given. It is not clear if the increase of binding strength of adalimumab to TNF was even statistically significant. Furtehrmore, the increase in binding affinity simply states a characterization of the results of the combination of adalimumab with methotrexate in a composition. There would be ample motivation to make a composition of adalimumab with methotrexate to treat autoimmune and inflammatory disease.
Claims 1, 2, 5-10, 21-26 and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US 2023/0312700, published October 5, 2023, effective filing date June 19, 2019, cited previously) in view of Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously) and Meyers et al (US 2021/0213201, published July 15, 2021, effective filing date August 7, 2020), Boldajipour et al (US 2023/0192839, published June 22, 2023, filing date March 29, 2018) and Hochberg et al (Ann Rheum Dis 62(Suppl II):ii13-ii16, 2003).
Jones disclose a pharmaceutical composition comprising a combination of methotrexate and adalimumab (paragraphs 67-77, 86, 89). Jones disclose that adalimumab is present in the formulation at a concentration of 100 mg/mL (paragraph 74, 2725). Jones disclose an injection device and vial for subcutaneous administration of a medicament comprising adalimumab (paragraphs 89, 321, 3248, 1665-1669, 1949-2008, 2725).
Jones does not specifically disclose methotrexate at a concentration of 5 milligrams per milliliter to 25 milligrams per milliliter or at a concentration of from 25 milligrams per milliliter to 50 milligrams or two injection devices.
Dave disclose injectable solutions comprising 20 mg methotrexate per 0.4 ml (50 mg/ml) (paragraphs 120, 121).
Myers disclose injectable solutions comprising methotrexate and adalimumab (paragraphs 9, 54, 241-254). Myers disclose that the medical injector may comprise one or two containers that can include either the same medicament or two different medicaments paragraphs.
One of ordinary skill in the art would have been motivated to apply Dave’s methotrexate concentrations and Myers’s dual container devices to Jones’s injection device comprising a pharmaceutical composition comprising a combination of methotrexate and adalimumab because Jone, Dave and Myers all disclose injection devices comprising methotrexate and an anti-TNF antibody. It would have been prima facie obvious to combine Jones’s injection device comprising a pharmaceutical composition comprising a combination of methotrexate and adalimumab with Dave’s methotrexate concentrations and Myers’s dual container devices to have an injection device for subcutaneous administration comprising a fluid reservoir containing a pharmaceutical composition comprising methotrexate at a concentration of 5 milligrams per milliliter to 50 milligrams per milliliter and adalimumab at a concentration of 20 milligrams per milliliter to 100 milligrams per milliliter.
In addition, Hochberg discloses Weinblatt added adalimumab at a dose of 20, 40, or 80 mg every other week by subcutaneous injection to 271 patients with RA who had been receiving methotrexate at their maximal tolerated dose of between 12.5 and 25 mg/week (ii14, 2nd column). Hochberg disclose Keystone added adalimumab at a dose of 20 mg weekly to 619 patients with RA who had been receiving methotrexate at their maximal tolerated dose (Id). Thus, Houchberg discloses mass ratios of methotrexate (12.5 – 25 and adalimumab that fall within the claimed mass ratios of the biopharmaceutical and methotrexate.
Furthermore, the limitations the pharmaceutically active biopharmaceutical and the methotrexate are present in a mass ratio of 10:1 to 1:10, 6:1 60 1:3 or 3:1 to 1:1. in the composition, the mass ratio of the composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "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."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); 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).
Neither Jones, Myers nor Dave disclose that the derivative of methotrexate has a structure of methotrexate but with a different atom or functional group in place of a hydrogen atom.
Boldajipour disclose a methotrexate that has been pegylated to improve the properties of the methotrexate. (paragraph 96).
One of ordinary skill in the art would have motivated to apply Boldajipour’s disclosure of a modified methotrexate to Jones, Myers and Dave’s composition comprising adalimumab and methotrexate because Boldajipour discloses that pegylation of methotrexate improves the properties of methotrexate. It would have been prima facie obvious to combine Jones, Myers and Dave’s composition comprising adalimumab and methotrexate with Boldajipour’s disclosure of a modified methotrexate to have a pharmaceutical composition comprising methotrexate and adalimumab wherein adalimumab and methotrexate are present in a mass ratio of 10:1 to 1:10 in the composition: and wherein the derivative has a structure of methotrexate but with a different atom or functional group in place of a hydrogen atom.
Applicant states that [0067]-[0077] of Jones, as cited by the Office, a formulation comprising a TNF alpha inhibitor, which may be an antibody such as adalimumab is disclosed. Applicant states that [0078]. of Jones relates to a method of treatment wherein an additional agent is administered in addition to the TNF inhibitor. The additional agent may be administered topically or by another form of administration. Applicant argues that among a large number of options, methotrexate is mentioned as a possible additional agent. Applicant argues that in sharp contrast to the Office's assumption, Jones discloses a conventional combination therapy based on co-administration of a TNF inhibitor and, separately, methotrexate.
Applicant’s arguments have been considered but are not persuasive. Jones discloses a formulation of adalimumab is administered to a patient in combination with methotrexate (paragraph 471). Jones discloses the formulation of adalimumab and methotrexate are administered to a patient simultaneously or consecutively. Jones discloses that the formulation of adalimumab and methotrexate is administered to a patient in the same dosage form (Id). Thus Jones does a composition comprising adalimumab and methotrexate.
Applicant also argues unexpected results of the pharmacological properties of the composition according to amended claim 1. Applicant argues that this applies all the more to the inventive interaction of these effects, which, compared with the cited references, leads to improved efficacy, tolerability and reliability of the claimed composition
In response as discussed previously, the results of Figure 2 and the table on page 35 discloses that adalimumab, etanercept, abatacept, infliximab and golimumab had different denaturation temperatures and relative increases in binding strength in the presence of methotrexate. Thus, the unexpected results described by Applicants are not commensurate in scope with the breadth of the claims as currently presented. The claims recite a composition comprising any biopharmaceutical composition. However, the specification only discloses the improvement of a couple of properties of five antibodies in the presence of methotrexate.
It is noted that methotrexate only increases the relative binding strength of adalimumab to TNF from 147.3 pm to 139.7 pm with no standard deviations given. It is not even clear if the increase of binding strength of adalimumab to TNF was statistically significant. Furtehrmore, the increase in binding affinity simply states a characterization of the results of the combination of adalimumab with methotrexate in a composition. There would be ample motivation to make a composition of adalimumab with methotrexate to treat autoimmune and inflammatory disease.
Claims 1, 2, 5-10, 21-27 and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US 2023/0312700, published October 5, 2023, effective filing date June 19, 2019, cited previously) in view of Dave et al (US 2013/0058930, March 7, 2013, IDS, cited previously), Meyers et al (US 2021/0213201, published July 15, 2021, effective filing date August 7, 2020, cited previously), Boldajipour et al (US 2023/0192839, published June 22, 2023, filing date March 29, 2018) and Hochberg et al (Ann Rheum Dis 62(Suppl II):ii13-ii16, 2003) in further view of Murphy et al (US 2020/0164087, published May 28, 2020, IDS, cited previously).
Neither Jones, Dave, Boldajipour, Hochberg nor Myers disclose a drug-loaded nanoparticle or microparticle comprising the pharmaceutical composition comprising methotrexate and an active pharmaceutical.
Murphy disclose mineral coated microparticles for sustained delivery of biologically active molecules (paragraphs 9-14). Murphy discloses that suitable biologically active molecules include adalimumab and infliximab (paragraph 111).
One of ordinary skill in the art would have been motivated to apply Murphy’s mineral coated microparticles to Jones, Dave, Boldajipour, Hochberg and Myers injection device comprising a pharmaceutical composition comprising methotrexate and adalimumab because Murphy discloses suitable active agents include infliximab, adalimumab and methotrexate (paragraphs 9-16, 51, 87) and recites that the microparticle would provide sustained delivery and/or local delivery of biologically active molecules and could be used to treat autoimmune and inflammatory disease (Id). It would have been prima facie obvious to combine Jones, Dave, Boldajipour, Hochberg and Myers injection device comprising a pharmaceutical composition comprising methotrexate and adalimumab with Murphy’s mineral coated microparticles comprising adalimumab and methotrexate to have a drug-loaded microparticle comprising methotrexate and adalimumab.
Summary
Claims 1, 2, 5-10, 21-27 and 33-35 stand rejected
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark Halvorson whose telephone number is (571) 272-6539. The examiner can normally be reached on Monday through Friday from 9:00 am to 6:00 pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at (571) 272-8149. The fax phone number for this Art Unit is (571) 273-8300.
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646
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