DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s request for Examiner to permit Applicant to shift the pending claims to the subject matter of Group II of the Restriction Requirement, drawn to a method of manufacturing a suspension formulation, is acknowledged. As the subject matter of Group I, drawn to a suspension formulation, was presented in the form of a product-by-process, shifting the pending claims to the subject matter of Group II does not result in additional burden and further simplifies the comparison between the instantly claimed invention and the prior art, Applicant’s request is granted, and examination will shift to the subject matter of Group II.
Status of Claims
The amendments and arguments filed 18 March 2026 are acknowledged and have been fully considered. Claims 1-2, 5, 9-11, 15-17, 19, 21-23, 27-29, and 31 are currently pending. Claims 1-2, 5, 10, 15, 21-23, 27-29, and 31 are amended; claims 3-4, 6-8, 12-14, 18, 20, 24-26, 30, and 32-37 are cancelled; no claims are withdrawn; no claims are new.
Claims 1-2, 5, 9-11, 15-17, 19, 21-23, 27-29, and 31 are examined on the merits herein.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities:
claim 1 has two periods, one at the end of step (e) and one at the end of the final line; and
claim 1 recites the non-aqueous vehicle comprising a semifluorinated alkane twice, once in step (d) and once in the final line of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites in step (e) the broad recitation “homogenizing the suspension formulation”, and the claim also recites “preferably by high-shear homogenization, milling, or ultrasonication” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For examination purposes, the narrower limitation is interpreted as being merely exemplary of the remainder of the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 10-11, 16-17, 19, 21-23, 27-28, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Günther et al. (US 2016/0159902; of record) in view of Zhou et al. (Drying Technology, 2014, Vol. 32, 1840-1847).
Claim 1 is drawn to a method for the manufacture of a suspension formulation comprising a protein particle and a non-aqueous vehicle, the method comprising the steps of:
providing an aqueous solution comprising a protein and a stabilizing agent,
removing the water from said aqueous solution to obtain solid protein particles,
further drying the protein particles obtained in step (b) to obtain protein particles comprising a residual water content of less than 0.5 wt%, based on the weight of the particle,
suspending the protein particles of step (c) in a non-aqueous vehicle comprising a semifluorinated alkane, and optionally
homogenizing the suspension formulation,
wherein the protein particle comprises a protein and a stabilizing agent, and wherein the non-aqueous vehicle comprises a semifluorinated alkane.
Claim 2 is drawn to the method of claim 1, wherein the water in step (b) is removed by lyophilizing the composition.
Claims 10 and 28 are drawn to the method of claim 1, wherein the protein particles in step (d) are resuspended in F6H8.
Claims 11 and 23 are drawn to the method of claim 1, wherein the stabilizing agent is a saccharide or a polyol.
Claim 22 is drawn to the method of claim 1, wherein the water in step (b) is removed by lyophilizing and the drying in step (c) is vacuum drying.
Günther et al. teach compositions of antibodies in semifluorinated alkanes (Abstract), wherein the compositions are suspensions of protein particles (Par. [0023]). Günther et al. further teach in Example 1 (Pars. [0073-74]) a method of producing a suspension of an anti-ECSCR antibody in F6H8 comprising:
providing a solution of anti-ECSCR antibody in PBS buffer,
lyophilizing the anti-ECSCR antibody,
–
suspending the anti-ECSCR antibody in F6H8.
Günther et al. further teach in Par. [0062] the compositions being free from water, and in Par. [0071] homogenization of the suspension to adjust the protein particle size.
As such, Günther et al. teach a method for the manufacture of a suspension formulation comprising a protein particle and a non-aqueous vehicle, the method comprising the steps of: providing an aqueous solution comprising a protein, removing the water from said aqueous solution to obtain solid protein particles, obtaining protein particles comprising a residual water content of less than 0.5 wt%, based on the weight of the particle, suspending the protein particles oin a non-aqueous vehicle comprising F6H8, and optionally homogenizing the suspension formulation, wherein the protein particle comprises a protein, and wherein the non-aqueous vehicle comprises F6H8.
The method of Günther et al. differs from the instantly claimed method in the following ways:
the solution of step (a) of Günther et al. does not comprise a stabilizing agent;
Günther et al. do not teach a secondary drying step;
Günther et al. do not teach the residual water content of the protein particles; and
the method of Günther et al. does not comprise a homogenization step.
Yet, as to 1: Günther et al. further teach “It should be noted that the lyophilization process step itself may induce aggregation and/or degradation. Additional stabilizing excipients such as saccharides or polyols are often added to the pre-lyophilization composition, along with other excipients such as bulking agents” (Par. [0009]).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. to include a stabilizing agent in the solution of step (a). It would have been obvious to combine the known method of manufacturing a protein suspension with the known use of a stabilizing excipient pre-lyophilization to yield the predictable result of a method for manufacturing a stabilized protein suspension, with a reasonable expectation of success.
As to 2: Zhou et al. teach combined drying methods for proteins (Title, Abstract). Zhou et al. further teach that freeze drying followed by vacuum drying reduce the drying time and energy consumption for the overall drying process while maintaining product quality (Pg. 1846 right column first paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. to include a secondary drying step as taught by Zhou et al. It would have been obvious to use the known combined freeze drying and vacuum drying technique to improve the method of Günther et al. in the same way by decreasing drying time and energy consumption, with a reasonable expectation of success.
As to 3: Günther et al. further teach exclusion of water as a step toward preparing a stable formulation of an antibody (Par. [0006]) and the composition being water free or substantially water free (Par. [0062]).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. to remove the water from the protein particles. It would have been obvious to combine the known method of manufacturing an antibody suspension with the known exclusion of water to yield the predictable result of a method of manufacturing a stabilized antibody suspension, with a reasonable expectation of success.
And, as to 4: Günther et al. further teach homogenization of the composition to adjust the protein particle size (Par. [0071]).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. to include a step of homogenization. It would have been obvious to combine the known method of manufacturing an antibody suspension with the known method for adjusting particle size in a suspension via homogenization to yield the predictable result of a method of manufacturing an antibody suspension having the desired particle size, with a reasonable expectation of success.
Based on all of the foregoing, claims 1-2, 10-11, 22-23, and 28 are rejected as prima facie obvious.
Claim 16 is drawn to the method of claim 1, wherein the protein concentration in the suspension formulation is between 2 and 350 mg/mL.
Claim 17 is drawn to the method of claim 1, wherein the total solid content of the suspension formulation is between 7 and 500 mg/mL.
Günther et al. further teach the protein concentration in the suspension of at least 5 mg/mL or at least 35 mg/mL (Par. [0053]), overlapping with the instantly claimed ranges.
As such, claims 16-17 is rejected as prima facie obvious.
Claim 19 is drawn to the method of claim wherein the residual water content of the suspension formulation is less than 1.0 mg/mL based on the total volume of the formulation.
Günther et al. further teach exclusion of water as a step toward preparing a stable formulation of an antibody (Par. [0006]) and the composition being water free or substantially water free (Par. [0062]).
As such, claim 19 is rejected as prima facie obvious.
Claim 21 is drawn to the method of claim 1, wherein after step (b) the residual water content of the protein particles is 3 to 5 wt%.
Günther et al. further teach that water mediates reactions that can cause the protein to aggregate or degrade (Par. [0006]), indicating that the amount of water in the protein particles is a result-effective variable, determining the stability of the protein in the composition.
As discussed by MPEP 2144.05, “[g]enerally, 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” (see also In re Aller (220 F.2d 454)): “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…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he 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” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the concentration of water in the protein particles is clearly a result-effective variable, determining the stability of the protein. Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal concentration of water in the protein particles in order to best achieve the desired results.
As such, claim 21 is rejected as prima facie obvious.
Claim 27 is drawn to the method of claim 1, wherein the semifluorinated alkane is F4H5.
Günther et al. further teach preferred semifluorinated alkanes including F4H5 and F6H8 (Par. [0029]).
As such, claim 27 is rejected as prima facie obvious.
Claim 31 is drawn to the method of claim 1, wherein the suspension formulation is free of a surfactant.
Günther et al. further teach “ In contrast to some other suspensions or dispersions known in prior art, the formulations of the invention require no surfactant, or only small amounts of surfactant, for their physical stabilization. This is a significant advantage as surfactants have a substantial potential for irritation and local toxicity, especially when administered by subcutaneous or intramuscular injection or by instillation into the eye. According to one of the preferred embodiments, the compositions of the invention are substantially free of surfactant” (Par. [0063]).
As such, claim 31 is rejected as prima facie obvious.
Claims 9 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Günther et al. and Zhou et al. as applied to claims 1-2, 10-11, 16-17, 19, 21-23, 27-28, and 31 above, and further in view of Hill et al. (US 2011/0223208 cited on Applicant’s IDS filed 23 May 2022).
The teachings of Günther et al. and Zhou et al. have been set forth above.
Claim 9 is drawn to the method of claim 1, wherein the relative weight ratio of the protein to the stabilizing agent in the protein is between 1:1 and 7:3.
Günther et al. and Zhou et al. do not teach the ratio of the protein to the stabilizing agent.
Hill et al. also teach non-aqueous suspensions of antibodies (Abstract, claim 8) comprising stabilizing excipients such as a saccharide (Par. [0050]). Hill et al. further teach the ratio of stabilizer to protein in the range of 1.18:1 to 2.17:1 (Table 5) as calculated by examiner, overlapping with the instantly claimed range.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. and Zhou et al. to have the relative weight ratio of the protein to the stabilizing agent in the protein between 1.18:1 and 2.17:1 as taught by Hill et al. It would have been obvious to combine the known method of manufacturing a protein suspension composition with the known weight ratio of protein to stabilizer in non-aqueous suspension compositions to yield the predictable result of a method for manufacturing a protein suspension composition, with a reasonable expectation of success.
As such, claim 9 is rejected as prima facie obvious.
Claim 15 is drawn to the method of claim 1, wherein at least 90% of the protein particles have a mean diameter of between 1 and 30 µm as determined by laser diffraction.
Günther et al. and Zhou et al. do not teach the protein particles having a mean diameter between 1 and 30 µm.
However, Günther et al. teach that large protein particles can cause clogging of fine-gauge needles (Par. [0024]), further teaching using homogenization methods to modify the size of the protein particles (Par. [0071]) and the compositions being suitable for parenteral injection (Abstract).
Hill et al. teach protein particles having a size between 2 µm to 13 µm as being suitable for injection (Par. [0056]).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. and Zhou et al. to form a suspension of protein particles having a size between 2 µm to 13 µm as taught by Hill et al. It would have been obvious to combine the known protein suspension for injection with the known size of protein particles suitable for injection to yield the predictable result of a method for manufacturing a protein suspension composition suitable for injection, with a reasonable expectation of success.
As such, claim 15 is rejected as prima facie obvious.
Claim 29 is drawn to the method of claim 1, wherein the stabilizing agent is trehalose or sucrose.
Günther et al. and Zhou et al. do not teach the stabilizing agent being trehalose or sucrose. However, Günther et al. teaches saccharides as a stabilizing agent with the protein (Par. [0009]). Hill et al. teach suitable excipients for protein particles including sucrose and trehalose (Par. [0050]).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. and Zhou et al. to include sucrose or trehalose as the stabilizing agent. It would have been obvious to substitute one saccharide stabilizer taught to be suitable for non-aqueous protein particle suspensions for another to obtain the predictable result of a method for manufacturing a protein suspension composition, with a reasonable expectation of success.
As such, claim 29 is rejected as prima facie obvious.
Claims 5 is rejected under 35 U.S.C. 103 as being unpatentable over Günther et al. and Zhou et al. as applied to claims 1-2, 10-11, 16-17, 19, 21-23, 27-28, and 31 above, and further in view of Kumar et al. (Int. J. Pharm., 2009, Vol. 366, 88-98).
The teachings of Günther et al. and Zhou et al. have been set forth above.
Claim 5 is drawn to the method claim 1, wherein the step (c) drying is vacuum drying conducted at a temperature of between 15-40 °C at a pressure of between 0.01-100 mbar.
Günther et al. and Zhou et al. do not teach vacuum drying conducted at a temperature of between 15-40 °C at a pressure of between 0.01-100 mbar.
However, Kumar et al. teach vacuum drying of an antibody to obtain a dry and stable composition (Title). Kumar et al. further teach vacuum drying at a temperature of 25 °C at a pressure of 100 mTorr (Sec. 2.5 on pg. 91), corresponding to a pressure of 0.133 mbar as calculated with examiner, overlapping with the instantly claimed ranges.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Günther et al. and Zhou et al. to utilize the vacuum drying conditions of Kumar et al. It would have been obvious to combine the known method for drying proteins with known conditions for vacuum drying proteins to yield the predictable result of a method for manufacturing a stable protein suspension composition, with a reasonable expectation of success.
As such, claim 5 is rejected as prima facie obvious.
Response to Arguments
Applicant’s arguments with respect to claim 1 have been considered but are moot in view of the new ground of rejection set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Paul Hoerner whose telephone number is (571)270-0259. The examiner can normally be reached Monday - Friday 9:00am - 5:00pm eastern.
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/PAUL HOERNER/Examiner, Art Unit 1611 /CRAIG D RICCI/Primary Examiner, Art Unit 1611
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