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 .
Claims Status
The amendments filed on 08/20/2025 are acknowledged.
Claims 1-8, 12-19, and 23-26 are pending.
Claims 9-11 and 20-22 are canceled.
Claims 1-8, 12-19, and 23-26 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/20/2025 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Maintained Rejections
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.
Claims 1-8, 12-19, and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Kehry (WO2016123521; 01/02/2024 PTO-892) in view of Straub (WO2017015622; 01/02/2024 PTO-892), Shealey (EP 0417191; 02/20/2025 PTO-892), Kaisheva (US 20030138417; 02/20/2025 PTO), and Das (US 20110027262; 02/20/2025 PTO-892).
Regarding claims 1-7, 12-18, and 23, Kehry teaches an antibody containing a light chain variable region with the sequence of SEQ ID NO: 19 and a heavy chain variable region with the sequence of SEQ ID NO: 24 [page 22, lines 25-37].
SEQ ID NO: 19 has 100% sequence identity to SEQ ID NO: 1 of the instant application and SEQ ID NO: 24 has 100% sequence identity to SEQ ID NO: 2 of the instant application.
Kehry further teaches a pharmaceutical composition containing a therapeutically effective amount of the antibody, and that the composition can contain one or more pharmaceutically acceptable carriers or excipients, including buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates, which can be formulated by methods known to those skilled in the art [page 26, lines 24-36, claim 22]. Kehry also teaches recovering the antibody, in the method of preparation thereof, at a concentration of 1-100, 1-50, 1-25, 2-50, 5-50, or 2-20 mg/ml [page 9, lines 1-7]. Kehry further teaches that 0.02 M Sodium phosphate buffer was used for all dilutions [page 29, line 30]. 0.02 M is equivalent to 20 mM.
However, Kehry does not teach that the pharmaceutical composition also comprises 20-30 mM sodium chloride or 20-30mM sodium succinate, 80-100 mg/ml Trehalose, and 0.10-0.005% w/v Polysorbate 80, buffered at pH 6.5.
Straub teaches antibodies that bind GDF11 [0008] and that the antibody also binds to neonatal FC receptor (FcRn) [0072]. Straub also teaches that the antibody can be can be incorporated into a pharmaceutical composition, and can be prepared as an injectable solution that includes the antibody at a concentration of 0.1-250 mg/ml, which can be composed of either a liquid or lyophilized dosage [00332]. Straub further teaches that the composition comprises a buffer, which can be sodium phosphate or sodium succinate, sodium chloride, which can be used to modify the toxicity of the solution, at a concentration of 0-300 mM, a cryoprotectant, which can be trehalose, and a bulking agent, which can be 0-0.05% polysorbate-80 [00332]. Straub further teaches that trehalose can help protect and/or stabilize the antibody structure in the formulation [00526] and that polysorbate 80 can reduce protein aggregation [00525]. Straub also discusses that the pH ranges from 5.0-7.0, optimally 6.0 [0332]. Straub additionally teaches the compositions using one or more excipients are formulated to increase stability [00492] and that the relative amounts of active ingredients, pharmaceutically acceptable excipients, and/or additional ingredients in pharmaceutical compositions of the present disclosure may vary, depending upon identity, size, and/or condition of subjects being treated and further depending upon routes by which pharmaceutical compositions may be administered [00497].
Shealey teaches an aqueous stabilizing buffer containing an antibody or antibody fragments that inhibits the antibody or antibody fragments in solutions from precipitating and forming particulates [page 2, lines 57-58 – page 3, line 1] and teaches that the solution contains sodium phosphate at about 10mM to about 100mM [page 3, lines 14-17].
Kaisheva teaches an antibody formulation developed by selecting the optimum solution pH, buffer type and concentration, evaluating the effect of various excipients of the liquid stability, and optimizing the concentration of the screened excipients [0047] and that the compositions minimize the formation of antibody aggregates and particulates and ensure that the antibody maintains its bioactivity over time [0048]. Kaisheva further teaches that a buffer of pH 6.0-6.5 is preferred and that a preferred buffer contains about 20-60 mM sodium succinate [0050].
Das teaches stable antibody formulations comprising a chelating agent and additional pharmaceutically acceptable excipients including one or more buffers, tonicity agents, surfactants, antioxidants, and mixtures thereof [0085]. Das further teaches that the tonicity agent can be trehalose [0190] and the trehalose is present in the composition at a concentration of about 90 mg/mL [0193]. The Examiner is interpreting the “about 90 mg/mL” as encompassing 90.5 mg/mL of Trehalose, absent evidence to the contrary.
It would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have placed the antibody of Kehry into the pharmaceutical composition of Straub. One would have been motivated to make this modification because Straub teaches that the composition is formulated to increase stability. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” Moreover, it would have been obvious to select either sodium phosphate or sodium succinate as the buffer because Straub teaches that both are buffers and are suitable for formulating antibody compositions. These are art recognized equivalents, and so, it is prima facie obvious to substitute equivalents known for the same purpose (see MPEP 2144.06 (II)).
Additionally, one of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to optimize the composition to comprise
the antibody at a concentration of 10 or 30 mg/ml, as taught by Kehry, 25 mM of sodium phosphate or sodium succinate, as taught by Shealey and Kaisheva, respectively, 25 mM of sodium chloride, as taught by Straub, 0.01% w/v Polysorbate 80, as taught by Straub, and 90.5 mg/ml of trehalose, as taught by Das, because the prior art references all teach that these are values within the acceptable ranges for each of the excipients for formulating stable antibody compositions. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” Further, because these are art recognized variables and therefore, one would engage in routine optimization to obtain the desired result of a stable formulation for the composition, thus arriving at these specific concentrations as claimed. See MPEP 2144.05 (II). Further, 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. “[Where 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). The determination of specific excipients at specific concentrations in the instant composition requires only routine experimentation for one of ordinary skill in the art. Therefore, given that the excipients at the claimed ranges and values are common to include in the formulation of antibody compositions, as taught in the art above, without specific evidence that the indicated concentrations are critical to the formulation, the identification of these properties will not render the subject matter patentable.
Regarding claims 8, 19, and 24-26, it further would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have selected the particular excipients, as taught by Straub, Shealey, Kaisheva, and Das thereby arriving at the invention as claimed (i.e. a pharmaceutical composition comprising an antibody, sodium phosphate or sodium succinate, sodium chloride, Trehalose, and Polysorbate 80, wherein the composition does not comprise anything else) because these are known excipients in the art for stabilizing pharmaceutical compositions.
Response to Arguments
The rejections of claims 1-8, 12-19, and 23-26 under 35 U.S.C. 103 over Kehry, Straub, Shealey, Kaisheva, and Das are maintained. On page 6 of the remarks, Applicant argues that the office fails to identify any disclosure in Straub that would have prompted a person of ordinary skill who was aware of Kehry's anti-FcRn antibody to use the specifically claimed combination of buffers, excipients, and surfactants because Straub does not mention using all of the excipients together in a single formulation and rather, the claimed excipients instead appear in lists among many other allegedly "suitable" excipients for generic pharmaceutical compositions in liquid or lyophilized dosage forms. This is not found persuasive because as previously addressed in the office action mailed 02/20/2025, the fact that these are not found in a single composition is an argument against anticipation, which is not the basis of this rejection. Additionally, the lack of a working example is not an indication of non-enablement. Prior art is presumed enabled (see MPEP 2121(I)), and a disclosure of alternatives does not dissuade from any one alternative. Applicant further argues that Shealey does not cure the deficiencies of Kehry and Straub because Shealey fails to disclose sodium phosphate in combination with the presently claim excipients, and does not disclose sodium phosphate at a concentration of 25 mM because Shealey only describes a range of sodium phosphate in combination with unclaimed excipients and does not teach or suggest a formulation for an anti-FcRn antibody. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner relied on the teachings of Shealey to teach a range of sodium phosphate because it teaches that the claimed value of 25 mM is a value within the acceptable range for the excipient in order to formulate stable antibody compositions. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” See rejection above. Further, as the Examiner articulated in the previous rejection and rejection above, because the concentration of sodium phosphate is an art recognized variable, which is supported by Shealey teaching a range for the concentration, one would engage in routine optimization to obtain the desired result of a stable formulation for the composition, thus arriving at the specific concentration as claimed. See MPEP 2144.05 (II). The argument that there is no single, specific concentration taught in the art is not an argument against the rationale that the excipients are routine effective variables and would engage in routine optimization.
Further on page 6 of the remarks, Applicant argues that Kaisheva also does not cure the deficiencies of Kehry and Straub because like Shealey, Kaisheva only provides a range of sodium succinate, none of the specified formulation include 25 mM sodium succinate, and does not teach or suggest a formulation for an anti-FcRn antibody. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The Examiner relied on the teachings of Kaisheva to teach a range of sodium succinate because it teaches that the claimed value of 25 mM is a value within the acceptable range for the excipient in order to formulate stable antibody compositions. MPEP 2144.05 (I) states “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facia case of obviousness exists.” See rejection above. Further, as the Examiner articulated in the previous rejection and rejection above, because the concentration of sodium succinate is an art recognized variable, which is supported by Kaisheva teaching a range for the concentration, one would engage in routine optimization to obtain the desired result of a stable formulation for the composition, thus arriving at the specific concentration as claimed. See MPEP 2144.05 (II). The argument that there is no single, specific concentration taught in the art is not an argument against the rationale that the excipients are routine effective variables and would engage in routine optimization. Applicant also argues that the Das does not cure the deficiencies of Kehry and Straub because Das does not disclose the combination of trehalose with the claimed excipients and does not teach compositions with anti-FcRn antibodies. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues on page 7 of the remarks that Straub, Shealey, Kaisheva, and Das do not teach use of the claimed excipients together in a single formulation and therefore, one would not have arrived at the claimed composition without an impermissible use of the hindsight. In response to Applicant’s argument that the Examiner used improper hindsight reasoning, Applicant has not pointed to any fact that has been obtained only from Applicant’s disclosure. These are known reagents to be optimized in the pharmaceutical composition art as taught by Straub, Shealey, Kaisheva, and Das. Further, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant argues this response to their hindsight argument stating that the Office’s impermissible reliance on Applicant’s disclosure is demonstrated by the fact that it is the only document of record that discloses the claimed combination of excipients at the specific claimed ranges, that there is an absence of such disclosure in any of the cited publications, and further argues that the Office seems to be improperly requiring that at least one of the components of a formulation needs to be unknown for the formulation to be patentable. This is not found persuasive because again, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The rejection has set forth that the claimed excipients at the claimed ranges are known in the art and that the ranges of concentrations for each demonstrates that these are result effective variables that would engage in routine optimization, which is a valid ground for an obviousness rejection. In response to Applicant’s argument that the Office seems to be improperly requiring that at least one of the components of a formulation needs to be unknown for the formulation to be patentable, this is not found persuasive because no such requirement has been made.
Applicant further argues that the relevant inquiry is not whether the claimed components are known or unknown, but rather whether the skilled person would have combined the components into a single formulation with any reasonable expectation of success, and that the Office has pointed to no teaching or suggestion in the cited art regarding the desirability of the claimed combination of excipients in a single pharmaceutical composition. This is not found persuasive because according to KSR, the standard is whether or not they could have been combined with any reasonable expectation of success. All claimed excipients at the claimed ranges are known in the art and are recognized in the art to be optimized on a per antibody basis for antibody pharmaceutical formulations. Applicant also argues that the mere fact that someone could have modified a prior art product to correspond to a patent claim does not mean that the modification would have been obvious. This is not found persuasive because the rejection sets forth why it would have been obvious to arrive at the claimed formulation, and Applicant continues to argue that a rejection under 35 U.S.C. 103 must be established on motivation, which is not the standard of 103. See KSR.
On page 8 of the remarks, Applicant argues that the presently claimed buffer components, excipients, and surfactants, at the recited concentrations, provide a stable composition comprising an antibody having the heavy chain of SEQ ID NO: 2 and the light chain of SEQ ID NO: 1 suitable for pharmaceutical administration, as evidenced by Examples 1-3 of the instant specification, and that without some specific guidance or suggestion, there is no reason to believe that a person of ordinary skill would have predicted the claimed combination, or the stability achieved by such a combination. This is not found persuasive because there is specific guidance and suggestion in the art cited that these are elements used to create stable antibody formulations, and the particular stability achieved by the formulation is the result of the routine optimization of these parameters. The art teaches that these are components of antibody pharmaceutical compositions that must be optimized to get the best results, which is what Applicant did, and therefore, would have been obvious for reasons of record. Applicant rebuts this argument stating that the office continues to allege that selection of the claimed excipients to achieve a stable antibody formulation was the result of routine optimization, which Applicant strenuously disagrees with, and which is not the law, referencing ModernaTx, Inc. v. Arbutus Biopharma Corp and HZNP Medicines LLC v. Actavis Laboratories UT, Inc as support for variables which interacted in an unpredictable or unexpected way could render the combination nonobvious. The specific citation of ModernaTx states that “in cases with multiple result-effective variables, '[e]vidence that the variables interacted in an unpredictable or unexpected way could (emphasis added) render the combination nonobvious.” While Applicant argues that they have demonstrated this, it is not over the range that Applicant is claiming and the Examiner cannot establish that unpredictability does not extend to other ranges not demonstrated. The fact that this could render nonobviousness is not controlling. The Examiner has established that these variables, to the extent that they interact and are known in the art, are predictable, and therefore, it is the optimization of these variables that results in the desired outcome. Applicant also argues that they have provided unrebutted evidence that the claimed excipients interact in unpredictable and unexpected ways, specifically claiming that the combination of Trehalose with only low concentrations of sodium chloride unexpectedly conferred stability and that buffering the claimed formulation to a pH of 6 or 6.5 produced improvements in size purity, charge heterogeneity and size distribution, and thus, as in ModernaTx, Applicant's evidence that the excipients interact in an unpredictable or unexpected way is sufficient to render the combination nonobvious. First, The Examiner did rebut the alleged unexpected results in a previous office action. See response to arguments in the office action mailed 06/13/2024. Second, these specific arguments are not found persuasive because there is nothing that demonstrates that the Trehalose with only low concentrations of sodium chloride unexpectedly conferred stability. Example 1 as set forth in the instant specification states that all formulations without Trehalose showed opalescence and all other formulations [with Trehalose] (including those with both 25 mM NaCl (i.e. low concentration) and 150 mM NaCl (i.e. high concentration)) remained colorless, clear, and free of visible particles, indicating that the Trehalose component confers satiability [see page 21, first paragraph]. Further, Applicants claim that buffering the claimed formulation to a specific pH produced improvements is a matter itself of routine optimization. The fact that these are variables that are recognized as needing to be optimized (i.e. in order to improve the composition) establishes that these conditions, when adjusted, lead to improved results. Optimizing conditions to obtain improved results is not equivalent to unexpected or unpredictable results.
Further on page 9 of the remarks, Applicant states that a person of ordinary skill in the art would have understood that there are countless combinations of antibodies, buffers, and excipients, including those that Kehry, Straub, Shealey, Kaisheva, and Das disclose, and that the contention that each buffer and excipient serves a known, predictable function is contrary to the understanding of those of skill in the pharmaceutical arts and is expressly contradicted by an abundance of evidence of record. This is not found persuasive because the Examiner has provided evidence supporting this stance which is the rejection of record. On page 10 of the remarks, Applicant again points to results of Example 1 to demonstrate that formulations with Trehalose were more stable than those without Trehalose, which was an outcome that was entirely unexpected and demonstrates the well-recognized unpredictability of the behavior of excipients in a pharmaceutical composition. This is not found persuasive because as the Examiner has set forth in the rejections of record, it is well-recognized that this is a predictable excipient in pharmaceutical formulations, and that it is necessary to optimize the parameters of pharmaceutical formulations in order to improve them. Additionally, it would not be unexpected that formulations with Trehalose were more stable than those without Trehalose. This is evidenced by Straub in the rejection above who teaches that trehalose can help protect and/or stabilize the antibody structure in the formulation [00526], Kaushik et al., 2003 (02/20/2025 PTO-892) who teaches that trehalose is a known stabilizer of proteins (i.e. antibodies) that helps retain the activity of enzymes in solution as well as in the freeze-dried state and can be expected to work as a universal stabilizer of protein conformation [see Abstract], and Onitsuka et al., 2014 (02/20/2025 PTO-892) who teaches that one of the hallmark effects of trehalose is anti-aggregation activity and that an analysis of various forms of an antibody showed that trehalose decreased the relative content of large aggregates by two thirds [see Abstract]. Thus, what Applicant claims as unexpected would actually be expected. Applicant further argues that formulations at pH 6.5 exhibited higher size purity, better maintenance of charge heterogeneity, and no significant increase in size distribution, and that the surprisingly beneficial properties of a formulation at pH 6 or 6.5 were unexpected. This is not persuasive because again, Applicants claim that buffering the claimed formulation to a specific pH produced improvements is a matter itself of routine optimization. The fact that the pH is a variable that is recognized as needing to be optimized (i.e. in order to improve the composition) establishes that these conditions, when adjusted, lead to improved results. Optimizing conditions to obtain improved results is not equivalent to unexpected results.
Further on pages 10-11 of the remarks, Applicant cites Sifniotis to demonstrate that the unpredictable behavior of a given excipient in a pharmaceutical composition is further compounded by the unique properties of the antibody with which is it combined, and argues that because the structural makeup of an antibody unpredictably influences the way it behaves in a formulation, there is no reason to believe that a person of ordinary skill in the art would have arrived at the claimed pharmaceutical composition with any reasonable expectation of success based on Straub's disclosure of pharmaceutical formulations for a different antibody. This is not found persuasive because Sifniotis actually recognizes additional reasons as to why these known parameters need to be optimized because the components of the pharmaceutical compositions are performing their known functions regardless of the properties of the antibody, and so, the composition will need to be optimized to best support the specific antibody formulation. Further, as the Examiner has already set forth and as Sifniotis also supports, every formulation requires optimization of the known components to achieve the best results.
On page 11 of the remarks, Applicant argues that Applicant’s showing of the criticality of the selection of excipients and ranges is sufficient to establish non-obviousness, pointing to the results of Table 1 in the instant specification. This is not found persuasive because again, the results Applicant points to do not support criticality, rather, the results only demonstrate that Applicant optimized the conditions to improve the pharmaceutical composition. An “increased stability” does not mean that the concentrations or excipients are critical to stability, rather they this is just the best formulation (i.e. an optimized formulation). Applicant further argues that Straub provides a range of 0-300 mM for sodium chloride, optimally 150 mM for a liquid dosage form, and as such, the preferred concentration for sodium chloride that Straub suggests produced inferior results in the claimed composition and is excluded from the claimed range of 20-30 mM. This is not found persuasive because inferior results is not evidence of criticality. Rather, it is evidence of optimization and that one would want to improve upon the already existing results. Further, a disclosure of a preferred embodiment does not undermine the full disclosure of Straub which still teaches an acceptable range of 0-300 mM for sodium chloride, thereby indicating that this is a result effective variable, and therefore Straub does teach the claimed range of 20-30 mM. Additionally, on page 12 of the remarks, Applicant argues that Straub does not recognize Trehalose as a potential stabilizer for liquid formulations. This is an incorrect characterization of the teachings of Straub. Straub clearly indicates that trehalose is a cryoprotectant [see 00332 of Straub], which is a stabilizer, and that trehalose can help protect and/or stabilize the antibody structure in the formulation [see 00526 of Straub]. Further, as already cited in the teachings of Straub, Kaushik, and Onitsuka, it is well known in the art that trehalose is a stabilizer, whether in solution or a freeze-dried state. Further, Straub does teach liquid formulations, specifically that the antibody can be prepared as an injectable solution, which can be composed of either a liquid or lyophilized dosage [see 00332 of Straub]. Further on page 12 of the remarks, Applicant argues that they discovered that the use of the claimed pH resulted in unexpectedly improved charge heterogeneity and stability over time, specifically that formulations at pH 6.5 were better than pH 7 and 7.5, and that pH 5 or 8 are not stable and may form degradation products over time. This is not found persuasive because again, inferior results are evidence of optimization and that one would engage in routine optimization to improve upon already existing results. To reiterate, inferior results does not mean nonobvious and does not mean unexpected. The state of art was such that optimizing these values was known for improving stability and various other aspects of antibody formulations. Thus, by optimizing these values, improved stability is obtained, and therefore, this is not unexpected.
On pages 12-13 of the remarks, Applicant argues that Applicant’s evidence of unexpected results achieved at the claimed ranges relative to the ranges supplied in Straub is sufficient to demonstrate non-obviousness, and that Applicant has shown (1) inclusion of Trehalose, (2) and a low concentration of sodium chloride (3) when buffered at a pH of 6.5 unexpectedly improves appearance, thermal stability, size purity, and charge heterogeneity of the claimed formulation, and therefore, is more than sufficient to rebut any prima facie case of obviousness. This is not found persuasive because Applicant is using the word unexpected to mean optimized. The art already demonstrates that all of the claimed excipients are known to be in specific ranges in pharmaceutical compositions, and one must optimize these to arrive at a stable composition. Further on page 13 of the remarks, Applicant argues that a finding of obviousness is improper because Applicant has demonstrated that the claimed composition confers unexpected improvements in appearance, thermal stability, size
purity, and charge heterogeneity that are not taught or suggested the cited references, alone or in combination. This is not found persuasive because again, Applicant is using the word unexpected to mean optimized. The art already demonstrates that all of the claimed excipients are known to be in specific ranges in pharmaceutical compositions, and one must optimize these to arrive at a stable composition. Applicant has not established unexcepted results by the legal definition, and again, improvements are a matter of routine optimization and optimization is not the same as unexpected or unpredictable. Applicant additionally argues that the unique combination of properties that Applicant has shown would not have been achievable through routine optimization and that the simultaneous improvement in multiple parameters that do not necessarily go hand-in-hand is evidence of the inventiveness of the resulting composition, citing Rabia for support of this argument. However, this is not found persuasive because Applicant still does not demonstrate why this would not have been achievable through routine optimization when all of these excipients were well known, the ranges of each were known, and their purpose in antibody formulations were known. Applicant also argues that a demonstration of an unexpected improvement in stability alone would be sufficient to rebut any prima facie case. This is not persuasive because as has already been explained, Applicant’s results were not unexpected. Applicant is using the term unexpected to mean optimized, and improvements are a matter of routine optimization and optimization is not the same as unexpected. Applicant lastly argues that the Office’s apparent requirement that Applicant show improvement in more than one property or that the property be uncommon in the pharmaceutical arts is clearly against the controlling law. This is not persuasive because the Office has made no such requirement.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675