DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed o or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 2-6, 13, and 15-18 were cancelled in previous communication. Claims 21-29 have been cancelled.
Claims 1, 7-12, 14, and 19-20 are currently under examination.
All rejections not reiterated have been withdrawn.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7-12, 14, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bukrinski et al. (US20160250329A1, Published 09/01/2016) in view of Ritzen et al. (Journal of Chromatography B, Volume 856, Published 06/28/2007, Pages 343-347) further in view of Sigg et al. (EP2869813B1, Published 11/21/2018), further in view of Vázquez-Rey et al. (Biotechnol. Bioeng., 108: 1494-1508, Published 05/16/2011).
The claims are examined in view of the following species elections:
(B) Disaccharide as the saccharide;
Applicant’s Invention
Applicant’s claims are drawn to an ophthalmic composition comprising: 24 mg/ml to 26 mg/ml of Bevacizumab; 40 mM to 60 mM of a buffer selected from the group consisting of acetate buffer, histidine buffer and phosphate buffer, pH of the buffer being 6.0 to 7.0; 40 mg/mL to 70 mg/mL of a saccharide stabilizer selected form the group consisting of trehalose and sucrose; 0.2 mg/mL to 0.6 mg/mL of a non-ionic polysorbate surfactant; wherein the composition satisfies the following: limits of Bacterial Endotoxin Test (BET) in the composition is in the range of 0.001 to 0.16 EU/mg; b. a particulate matter is; iv. 1 to 50 particles ≥10 µm in diameter per ml, v. 0 to 5 particles ≥25 µm in diameter per ml, and, vi. 0 to 2 particles ≥50 µm in diameter per ml; and; c. the composition has an aggregate of 0.1 to 3.5% after 2 years storage.
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 1, 7, and 9-10, Bukrinski teaches in the example Media and solutions Antibody: Bevacizumab (Avastin®, Roche): 25 mg/mL in buffer (100 mg Bevacizumab, 240 mg α,α-trehalose dihydrate (i.e., disaccharide), 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and water for injection (USP) to make a volume of 4 mL) (paragraph [0311]). The examiner points out that 240 mg of trehalose divided by 4 mL equals 60mg/ml of trehalose (i.e., saccharide stabilizer) and 1.6 mg polysorbate 20 divided by 4 mL equals 0.4mg/ml of polysorbate 20 (i.e., non-ionic surfactant). The Tocris molarity calculator is based on the following equation: Mass (mg) = Concentration (mol/L) x Volume (mL) x Molecular Weight (g/mol), wherein 28mg of sodium phosphate = 42.70 mM x 4 ml x 163.94 g/mol of sodium phosphate, therefore the concentration of the buffer is 42.70 mM.
Regarding claim 8, Bukrinski teaches 1.6 mg polysorbate 20 in a 25 mg/mL in buffer Avastin (Bevacizumab) solution to make a volume of 4 mL (paragraph [0311]). Bukrinski also discloses in Example 2 that the pH of 51 mM sodium phosphate buffer is 6.2 (paragraph [0315]).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Bukrinski does not teach wherein the composition satisfies the following: limits of Bacterial Endotoxin Test (BET) in the composition is in the range of 0.001 to 0.16 EU/mg; b. a particulate matter is; iv. 1 to 50 particles ≥10 µm in diameter per ml, v. 0 to 5 particles ≥25 µm in diameter per ml, and, vi. 0 to 2 particles ≥50 µm in diameter per ml; and; c. the composition has an aggregate of 0.1 to 3.5% after 2 years storage (instant claim 1). Bukrinski also does not teach wherein the ophthalmic composition is packaged in a pre-filled syringe, with a fill volume of 140 microL to 200 microL (instant claim 11); wherein the composition is configured to intravitreal administration (instant claim 12); wherein the prefilled syringe comprises a needle with a gauge in the range of 29 to 34 gauge (instant claim 14); and wherein the pre-filled syringe is as single use pre-filled syringe (instant claims 19-20). However these deficiencies are cured by Ritzen, Sigg et al. and Vázquez et al.
Ritzen teaches in the last decade, about 20 different monoclonal antibodies
(mAbs) have been FDA approved for therapeutic use, wherein new mAbs for these purposes are currently in clinical trials or under development, of which many are expected to be approved
in the coming years (Introduction, first paragraph). Ritzen also teaches that one particular problem is the removal of endotoxin, wherein the risk of endotoxin contamination is further increased if transient expression (Introduction, second paragraph). Ritzen further teaches an efficient method to reduce protein-associated endotoxin, in which arginine is applied during a wash-step of Protein A bound antibodies. A reduction of endotoxin to a level below 0.2 EU mg-1 antibody could be achieved which meets the criteria for in vivo preclinical studies (Introduction, fifth paragraph). Ritzen continues to teach that here we demonstrate that washing of a mAb bound to an affinity resin with 0.5M arginine is an effective way for specific removal of protein-bound endotoxin. This method is reproducible at different scales and is easy to perform and monitor. It also allows good recovery and does not affect the activity of the protein (conclusion paragraph).
Sigg teaches a pre-filled syringe suitable for ophthalmic injections more particularly intravitreal injection (paragraph [0009]), wherein the syringe comprises ophthalmic solution which comprises a VEGF antagonist, namely ranibizumab (paragraph [0008]). Sigg also teaches two antibody VEGF antagonists have been approved for human use, namely ranibizumab and bevacizumab (paragraph [0019]). Sigg continues to teach the syringe according to the invention may also meet certain requirements for particulate content. The ophthalmic solution comprises no more than 2 particles ≥50µm in diameter per ml, no more than 5 particles ≥25µm in diameter per ml, and no more than 50 particles ≥10µm in diameter per ml (paragraph [0018]). Sigg further teaches the syringe according to the invention may have a shelf life up to 24 months or longer (paragraph [0034]). Sigg also teaches bevacizumab is used off-label in such ophthalmic indications at a concentration of 25mg/ml; typically at a dosage volume of 0.05ml (1.25mg) (paragraph [0017]). Sigg further teaches the syringe to have a nominal maximum fill volume of about 0.5ml (i.e., 500µl). Sigg continues to teach bevacizumab is typically at a dosage volume of 0.05ml (i.e., 50 µl) (paragraph [0017]). Sigg also teaches kits comprising the pre-filled syringes of the invention, wherein such a kit comprises a pre-filled syringe of the invention in a blister pack (paragraph [0031]). Sigg further teaches such a kit may further comprise a needle for administration of the VEGF antagonist, the needle is typical to use a 30-gauge x ½ inch needle, though 31-gauge and 32-gauge needles, and 33-gauge or 34-gauge needles could alternatively be used as well. Such kits may further comprise instructions for use (paragraph [0032]).
Vazquez-Rey teaches Monoclonal antibodies have proved to be a highly successful class of therapeutic products. Large-scale manufacturing of pharmaceutical antibodies is a complex activity that requires considerable effort in both process and analytical development. If a therapeutic protein cannot be stabilized adequately, it will lose partially or totally its therapeutic properties or even cause immunogenic reactions thus potentially further endangering the patients’ health. The phenomenon of protein aggregation is a common issue that compromises the quality, safety, and efficacy of anti-bodies and can happen at different steps of the manufacturing process, including fermentation, purification, final formulation, and storage (abstract). Vasquez- Rey also teaches Separation during down-stream processing is of particular interest as it provides the biggest opportunity to remove aggregates once they have been generated. Thus, different purification strategies can be effectively used to deal with increases in aggregate levels due to process-driven modifications or other unexpected changes that may occur during technology transfer and scale-up (page 1502, column 2). Vasquez-Rey further teaches during downstream manufacturing, chromatography is typically the step that mostly contributes to aggregate removals. The choice of a particular resin and mode of operation should be guided by fit and compatibility with the overall process purification train as well as an appropriate balance of productivity, yield, and product quality (Chromatography as a tool to reduce Aggregates levels).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have prima facie obvious to one of ordinary skill in the art at the time of filing to have limits of Bacterial Endotoxin Test (BET) in the composition in the range of 0.001 to 0.16 EU/mg in Bukrinski’s Antibody solution comprising bevacizumab. Bukrinski teaches in the example Media and solutions Antibody: Bevacizumab (Avastin®, Roche): 25 mg/mL in buffer (100 mg Bevacizumab, 240 mg α,α-trehalose dihydrate (i.e., disaccharide), 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and water for injection (USP) to make a volume of 4 mL) (paragraph [0311]). The artisan of ordinary skill would have been motivated to limit the amount of Endotoxins in Bukrinski’s Antibody solution because Ritzen teaches that an efficient method to reduce protein-associated endotoxin, in which arginine is applied during a wash-step of Protein A bound antibodies. A reduction of endotoxin to a level below 0.2 EU mg-1 antibody could be achieved which meets the criteria for in vivo preclinical studies (Introduction, fifth paragraph), as one particular problem is the removal of endotoxin, wherein the risk of endotoxin contamination is further increased if transient expression (Introduction, second paragraph). The skilled artisan would have had a reasonable expectation of success because Bukrinksi teaches a solution comprising Bevacizumab which is an antibody being administered into a patient (i.e., in vivo) and Ritzen teaches reducing protein associate endotoxin to a level below 0.2 EU mg-1 antibody could be achieved which meets the criteria for in vivo preclinical studies.
With regards to the limitation of claim 1 wherein the composition has a particulate matter is; iv. 1 to 50 particles ≥10 µm in diameter per ml, v. 0 to 5 particles ≥25 µm in diameter per ml, and, vi. 0 to 2 particles ≥50 µm in diameter per ml, it would have been obvious to one of ordinary skill in the art for Bukrinski’s Antibody solution comprising bevacizumab to have a particulate matter is; iv. 1 to 50 particles ≥10 µm in diameter per ml, v. 0 to 5 particles ≥25 µm in diameter per ml, and, vi. 0 to 2 particles ≥50 µm in diameter per ml. Bukrinski teaches in the example Media and solutions Antibody: Bevacizumab (Avastin®, Roche): 25 mg/mL in buffer (100 mg Bevacizumab, 240 mg α,α-trehalose dihydrate (i.e., disaccharide), 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and water for injection (USP) to make a volume of 4 mL) (paragraph [0311]). The artisan of ordinary skill would have been motivated to have such particulate matter sizes because Sigg teaches the syringe according to the invention may also meet certain requirements for particulate content. The ophthalmic solution comprises no more than 2 particles ≥50µm in diameter per ml, no more than 5 particles ≥25µm in diameter per ml, and no more than 50 particles ≥10µm in diameter per ml (paragraph [0018]). Sigg also teaches bevacizumab is used off-label in such ophthalmic indications at a concentration of 25mg/ml; typically at a dosage volume of 0.05ml (1.25mg) (paragraph [0017]). The skilled artisan would have had a reasonable expectation of success because Bukrinksi teaches a solution comprising Bevacizumab which is an antibody being administered into a patient via a syringe, wherein Bukrinski prevents or inhibits aggregates such as particulates (paragraph [0035]) in order to form a stable formulation (paragraph [0040]), and Sigg teaches the syringe according to the invention may also meet certain requirements for particulate content. The ophthalmic solution comprises no more than 2 particles ≥50µm in diameter per ml, no more than 5 particles ≥25µm in diameter per ml, and no more than 50 particles ≥10µm in diameter per ml (paragraph [0018]), wherein it is particularly important for the ophthalmic solution to have particularly low particle content (paragraph [0009]).
With regards to the limitations wherein the ophthalmic composition is packaged in a pre-filled syringe, with a fill volume of 140 microL to 200 microL; wherein the composition is configured to intravitreal administration; wherein the prefilled syringe comprises a needle with a gauge in the range of 29 to 34 gauge; and wherein the pre-filled syringe is as single use pre-filled syringe, it would have been obvious to one of ordinary skill in the art to have Bukrinski’s Antibody solution comprising bevacizumab packaged into a pre-filled syringe. Bukrinski teaches in the example Media and solutions Antibody: Bevacizumab (Avastin®, Roche): 25 mg/mL in buffer (100 mg Bevacizumab, 240 mg α,α-trehalose dihydrate (i.e., disaccharide), 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and water for injection (USP) to make a volume of 4 mL) (paragraph [0311]). Bukrinski also teaches that the method can include filling the composition into a container such as a syringe (paragraph [0120]) and administered by a syringe (paragraph [0127]). One would have understood in view of Sigg that a device and in particular syringe, more particularly to a small volume syringe such as a syringe suitable for ophthalmic injections (paragraph [0001]), wherein the ophthalmic solution comprises a VEGF-antagonist (paragraph [0008]), and wherein the syringe is filled with a dosage volume (i.e. the volume of medicament intended for delivery to the patent) of between about 0.01ml (i.e., 10µl) and about 1.5ml (i.e.,1500 µl) of a VEGF antagonist solution, wherein bevacizumab is used off-label in such ophthalmic indications at a concentration of 25mg/ml; typically at a dosage volume of 0.05ml (1.25mg) (paragraph [0017]). It would have been obvious to one of ordinary skill in the art to have the composition of Bukrinski packaged into a pre-filled syringe because Bukrinski teaches the Bevacizumab (Avastin®) solution for injection use, and Sigg teaches using the Avastin solution for ophthalmic injections, wherein the ophthalmic solution comprises a VEGF-antagonist (paragraph[0008]), and wherein the syringe is filled with a dosage volume (i.e. the volume of medicament intended for delivery to the patent) of between about 0.01ml (i.e., 10µl) and about 1.5ml (i.e.,1500 µl) of a VEGF antagonist solution, wherein bevacizumab is used off-label in such ophthalmic indications at a concentration of 25mg/ml; typically at a dosage volume of 0.05ml (1.25mg) (paragraph [0017]), therefore, the Avastin (i.e., bevacizumab) solution made by Bukrinski would be suitable for ophthalmic pre-filled syringes. The pre-filled syringe being a single use pre-filled syringe is not patentably defining over Bukrinski and Sigg because the pre-filled syringe being a single use syringe does not identify the amount that is to be delivered, as well as depending on how much of the composition was needed. The examiner also points out that the limitation of a single use syringe does not limit the ophthalmic composition and is an intended use of the syringe.
With regards to the limitation of claim 1, wherein the composition has an aggregate of 0.1 to 3.5% after 2 years storage, it would have been obvious to one of ordinary skill in the art to have the composition with an aggregate of 0.1 to 3.5% after 2 years of storage. Bukrinski teaches Aggregation of highly concentrated antibody compositions may result in production of aggregates such as dimers, multimers, polymers and/or particulates of antibodies which may cause adverse immunogenic reactions, may affect antibody activity, may affect dosing precision, and may affect pharmacokinetic properties of the antibody. Overall, antibody aggregation may result in compromised safety and efficacy (paragraph [0006]). Bukrinski also teaches prevention or inhibition of aggregates, wherein no aggregates are formed or a partial prevention or inhibition happens, wherein the composition may contain at most 99 to 0.1% of the aggregates (paragraph [0035)]. Bukrinski further teaches a formulation in which the antibody contained therein following storage for at least 1-5 years contains at least 1% point fewer antibody aggregates (paragraph [0040]). The artisan of ordinary skill would have been motivated to limit the amount of aggregates in Bukrinski’s antibody solution because Vasquez-Rey teaches Monoclonal antibodies have proved to be a highly successful class of therapeutic products. The phenomenon of protein aggregation is a common issue that compromises the quality, safety, and efficacy of anti-bodies and can happen at different steps of the manufacturing process, including fermentation, purification, final formulation, and storage (abstract). Vasquez-Rey also teaches numerous strategies are employed to minimize the level of aggregates in bio-therapeutics including protein engineering, expression system selection, optimization, separation during downstream processing, and storage formulation buffer screening. Separation during down-stream processing is of particular interest as it provides the biggest opportunity to remove aggregates once they have been generated. Thus, different purification strategies can be effectively used to deal with increases in aggregate levels due to process-driven modifications or other unexpected changes that may occur during technology transfer and scale-up (page 1502, column 2). Vasquez-Rey further teaches during downstream manufacturing, chromatography is typically the step that mostly contributes to aggregate removals. The choice of a particular resin and mode of operation should be guided by fit and compatibility with the overall process purification train as well as an appropriate balance of productivity, yield, and product quality (Chromatography as a tool to reduce Aggregates levels). The skilled artisan would have had a reasonable expectation of success because Bukrinksi teaches a solution comprising Bevacizumab which is an antibody being administered into a patient and Vasquez-Rey teaches that monoclonal antibodies have the common issue of protein aggregates, Separation during down-stream processing is of particular interest as it provides the biggest opportunity to remove aggregates once they have been generated. Thus, different purification strategies can be effectively used to deal with increases in aggregate levels due to process-driven modifications or other unexpected changes that may occur during technology transfer and scale-up (page 1502, column 2); wherein during downstream manufacturing, chromatography is typically the step that mostly contributes to aggregate removals (Chromatography as a tool to reduce Aggregates levels).
Response to Arguments
Applicant’s arguments with respect to claim(s) 1, 7-12, 14, and 19-20 under 35 U.S.C. 103 have been considered but are moot because the new ground of rejection does apply to the rational underlying the obviousness conclusion. The new grounds of rejection necessitated by amendment have addressed the arguments. Insomuch as Applicant’s arguments are applicable to the new grounds of rejection, they are addressed here:
On pages 9-10 of Applicants remarks, Applicants argue that with the claims now amended to be commensurate with the data in the specification, the specification’s evidence of unexpected results is now directly applicable and provides compelling objective evidence of non-obviousness. The specification demonstrates that other repackaged bevacizumab compositions were unstable, showing significant degradation in as little as 6 months.
Insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims. The Examiner reiterates that Applicants have not shown a side by side comparison to the closest prior art, and that Applicants have not pointed to at least one of the references to show that the references pointed to in Tables 6 and 7 is the closest prior art. The Examiner also points out that the it is unclear for some of the references what all the ingredients are in their compositions, therefore a proper side-by-side comparison can’t be done.
The references pointed to by Applicants use repackaged bevacizumab whereas Applicants are claiming a pre-filled syringe, therefore the references cited in Tables 6 and 7 are not deemed the closest prior art. Lastly, the Examiner points out that Applicants have not met the burden to show how their instantly claimed ranges are critical and are tied to any allegedly unexpected property. For these reasons, no conclusions as to the unexpectedness of the data can be drawn.
Conclusion
No claims are allowed.
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 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.
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AFUA BAMFOAA BOATENGExaminer, Art Unit 1617 /ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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