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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 01/28/2026 has been entered.
Election/Restrictions
Applicant's election with traverse of Group I (i.e., claims 1-3, 5-7, 10 and 16-17, drawn to a composition) in the reply filed on April 23rd, 2024 is acknowledged. The traversal is on the ground(s) that the special technical feature (i.e., a synergistic optimum storage stable lyophilized composition consisting of pegaspargase in the rage of 2-32%, a cryoprotectant in the range of 9-91%, a bulking agent in the range of 1-78%, and a buffer in the range of 3-33%) is shared between claim 1 and claim 11. This is not found persuasive because as indicated in the restriction mailed on February 23rd, 2024, the shared technical feature between Group I and Group II is the scope of claim 1. Although claim 1 was amended to recite the percentages of the components (i.e., pegaspargase in the rage of 2-32%, a cryoprotectant in the range of 9-91%, a bulking agent in the range of 1-78%, and a buffer in the range of 3-33%), the scope of the claim remains unchanged. Therefore, the amendments made to claim 1 do not overcome the restriction requirement because the amended special technical feature is anticipated by CN105796507A published on July, 27th, 2016 (Cited in the IDS filed on 06/16/2021) as further articulated below.
Please note that restriction of Species A has been withdrawn.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on April 23rd 2024.
Examiner’s note: The action mailed on 06/23/2025 was inadvertently concluded to be final. However, the accompanying PTO-326 Office Action Summary dated 06/23/2025 indicated the status of the action as a non-final.
Status of Claims
Claims 1-17 were originally filed and amended on June 16th 2021. The amendment amended claims 1-15 and 17.
The amendment filed on April 23rd 2024, amended claims 1-2, 5-7 and 15; and cancelled claims 4 and 8-9.
The amendment filed on August 21st 2024, amended claims 1-2 and 11; cancelled claims 6 and 16; and added new claims 18-20.
The amendment filed on March 3rd 2025, amended claims 1, 3 and 18; and cancelled claims 10 and 20.
The amendment filed on September 23rd 2025, amended claim 1.
The amendment filed on January 28th 2026, amended claims 1 and 18.
Claims 1-3, 5, 7, 11-15 and 17-19 are currently pending, and claims 1-3, 5, 7 and 17-19 are under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/IN2019/050402 filed on May 20th 2019, and claims priority under 119(a)-(d) to Indian Application No. IN201821048859 filed on December 24th 2018.
Receipt is acknowledged of papers submitted under 35 U.S.C 119 (a)-(d) for Indian Application No. IN201821048859, which papers have been placed of record in the file.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 2, regarding the scope of “succinate linker,” it is noted that the instant specification teaches that Oncaspar® (i.e., Pegaspargase) was manufactured by pegylation of a 5 kDa monomethoxy polyethylene glycol (mPEG) Succinimidyl Succinate PEG, also referred to SS-PEG (see instant specification, pg. 2, paragraph 3). As such, the Examiner is interpreting SS-PEG as an example of the claimed “succinate linker”.
Response to Arguments
1. Applicants’ arguments, see Response, filed 01/28/2026, with respect to the Claim Interpretation, have been acknowledge.
2. Applicants’ arguments, see Response, filed 01/28/2026, with respect to 35 U.S.C. 103 as being unpatentable over CN105796507A (Machine Translation Google Patents and Machine translation from Espacenet) published on July 27th, 2016 (Cited in the IDS filed on 06/16/2021) (hereinafter “Chen”) as evidenced by as evidenced by Horn et al., European Journal of Pharmaceutics and Biopharmaceutics 127 (2018), pp. 342-354, available online March 5th 2018 (herein after “Horn 2”); in view of Horn et al., European Journal of Pharmaceutics and Biopharmaceutics 132 (2018), pp. 70-82, available online September 7th 2018 (herein after “Horn”); and Kantor et al., American Pharmaceutical Review, 2011, pp. 1-11, retrieved from https://www.americanpharmaceuticalreview.com/Featured-Articles/36901-Quality-by-Design-for-Freeze-Thaw-of-Biologics-Concepts-and-Application-to-Bottles-of-Drug-Substance/ on 06/14/2025 (herein after “Kantor”); have been fully considered and are persuasive. The 35 U.S.C. 103 rejection to claims 1, 3, 5, 7, 18 and 19 has been withdrawn.
3. Applicants’ arguments, see Response, filed 01/28/2026, with respect to 35 U.S.C. 103 as being unpatentable over CN105796507A (Machine Translation Google Patents and Machine translation from Espacenet) published on July 27th, 2016 (Cited in the IDS filed on 06/16/2021) (hereinafter “Chen”) as evidenced by Horn et al., European Journal of Pharmaceutics and Biopharmaceutics 127 (2018), pp. 342-354, available online March 5th 2018 (herein after “Horn 2”); in view of Horn et al., European Journal of Pharmaceutics and Biopharmaceutics 132 (2018), pp. 70-82, available online September 7th 2018 (herein after “Horn”); and Kantor et al., American Pharmaceutical Review, 2011, pp. 1-11, retrieved from https://www.americanpharmaceuticalreview.com/Featured-Articles/36901-Quality-by-Design-for-Freeze-Thaw-of-Biologics-Concepts-and-Application-to-Bottles-of-Drug-Substance/ on 06/14/2025 (herein after “Kantor”) as applied to claim 1 above, and further in view of WO2018/017190 A2, published on January 25th 2018 (Cited in the IDS filed on 06/16/2021) (hereinafter “Fornasini”); and US2012/0100121A1, published on April 26th 2012 (hereinafter “Abribat”); have been considered and are persuasive. The 35 U.S.C. 103 rejection to claims 2 and 17 has been withdrawn.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1. Claims 1-3, 5, 7 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
In the instant case, claim 1 was amended to recite “wherein a weight ratio of the amino acid bulking agent to the cryoprotectant is from 0.9 to 1.5.” Applicants stated in their remarks that “[s]upport for the amendments can be found throughout the specification, figures, and original claims of application 17/414,790 and parent application PCT/IN2019/050402. ” Further, Applicants stated that “no new matter has been added to the present application.” (See pg. 5 of 16 in the Remarks filed on 01/28/2026). However, the support (i.e., the specification, original claims of application 17/414,790 and parent application PCT/IN2019/050402) provided by Applicants does not support that the newly added limitation to claim 1 was previously presented, as the there is no mention of a weight ratio of from 0.9 to 1.5 of amino acid bulking agent to cryoprotectant.
The specification is void of support that would clearly support the newly added limitation. The specification does not teach the specifically claimed storage stable lyophilized composition wherein a weight ratio of the amino acid bulking agent to the cryoprotectant is from 0.9 to 1.5. Examination of the instant support shows that the envisioned compositions comprise cryoprotectant and bulking agent, and evaluates the effect of various bulking agents and cryoprotectants with varying percentages. However, there is no implicit or explicit data that would support the claimed amino acid bulking agent to cryoprotectant ratio. Positive recitation of compositions comprising amino acid bulking agent and cryoprotectant without any reference to whether the weight ratio of amino acid bulking agent to cryoprotectant is from 0.9 to 1.5 does not provide support in claiming that the claimed composition comprises the ratio. Therefore, the claimed composition having a weight ratio amino acid bulking agent to cryoprotectant from 0.9 to 1.5 is not expressly described.
MPEP 2105 states that “[a] lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. In the instant case, as set forth above, the disclosure describes the inclusion of pegaspargase in the range of 6-14%, cryoprotectant in the range of 32-41%, amino acid bulking agent in the range of 38-50%, and a buffer in the range of 4-6%, as part of the clamed composition. However, the specification is silent about the specific weight ratio of amino acid bulking agent to cryoprotectant. The tables depicted in the specification do not provide sufficient detail for an ordinary skill artisan to calculate the claimed ratio. As such, the instantly claimed composition comprising amino acid bulking agent and cryoprotectant in a ratio from 0.9 to 1.5 has not been adequately supported.
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness (Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
2. Claims 1, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over US2018/0099049 A1 Pub. Date: Apr. 12, 2018 (herein after “Tang”) as evidenced by Kozlowski et al. BioDrugs 2001; 15(7): 419-429 (herein after “Kozlowski”); in view of Wang. W., International Journal of Pharmaceutics 203 (2000) 1-60 (herein after “Wang”).
Regarding claim 1, Tang is in the field of stable lyophilized therapeutic protein compositions and their methods of manufacture (see front pg., abstract). Tang adds that the lyophilized form of the protein provides several advantages, one of which is maintaining the stability of the protein over time, especially for at least 18 months at room temperature (see pg. 10, para[0092]). Thereby constituting a storage stable lyophilized composition as recited in the preamble of instant claim 1.Tang’s composition comprises: (a) a protein, (b) a stabilizer, (C) a buffer (see pg. 17, claim 1), wherein said protein is present from about 6% to about 19% by weight (see pg. 17, claim 30).
As evidenced by Kozlowski, the chemical attachment of poly(ethylene glycol) (PEG) to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility (see pg. 419, Abstract). And that three PEG-protein conjugates are currently approved for clinical use in the US: pegademase, pegaspargase and pegylated interferon-α (see pg. 419, Abstract). Since Kozlowski provides evidence that pegaspargase constitutes a therapeutic protein, Tang’s stable lyophilized therapeutic protein compositions read on the instantly claim storage stable lyophilized composition comprising pegaspargase.
Additionally, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As such, the instantly claimed pegaspargase in the range of 6-14% lies inside Tang’s range (i.e., from about 6% to about 19% by weight). Therefore, the claimed composition comprising pegaspargase in the range of 6-14% would have been suggested to one skilled in the art.
Tang also teaches that lyoprotectants (a.k.a stabilizers), are often included in pre-lyophilization formulations to protect the protein against denaturation during the freeze-drying process (see pg. 1, para[0004]). Tang adds that the term “stabilizer” means a combination of chemical entities (i.e., more than one chemical entity) that together serve to stabilize the protein or other macromolecule (see pg. 2, para[0017]). Tang adds that the stabilizer is present at about 19% to about 83% by weight (see pg. 17, claim 12), that sugars are used as stabilizers (as well as bulking agents)(see pg. 6, para[0063]); and that amino acids are used as stabilizers, and glycine is a commonly used bulking agent and stabilizer (see pg. 6 para[0066]). Tang emphasizes that disaccharides trehalose and sucrose are relatively inert and tend to form an amorphous glass during lyophilization and that trehalose or sucrose, either alone or in combination with an amino acid or polyol, is used as a stabilizer in the practice of the lyophilized cake (see pg. 6, para[0063]).
As previously discussed, MPEP 2144.05(I), states that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Thus, the instantly claimed cryoprotectant in the range of 32-41% and the instantly claimed amino acid bulking agent in the range of 38-50% lie inside Tang’s stabilizer range (i.e., about 19% to about 83% by weight). Thereby, the claimed composition comprising a cryoprotectant in the range of 32-41% (i.e., stabilizer/lyoprotectant) and an amino acid bulking agent in the range of 38-50% (i.e., stabilizer/bulking agent), as recite in instant claim 19, would have been suggested to one skilled in the art.
Tang’s composition also comprises a buffer, which is included in the pre-lyophilization aqueous protein solution to stabilize the protein before lyophilization and after reconstitution (see pg. 6, para[0056]). Tang adds that the buffer is selected from a chemical capable of buffering somewhere within the pH range of about 3 to about 9, or within the pH range of about 3.7 to about 8.0 (see pg. 6, para[0058]). That buffer can be any buffer that maintains the optimal pH for protein stability; histidine is such a buffer, which has a pKa of about 6.0 and is capable of effectively buffering between pH 4.8 and 7.2 (see pg. 2, para[0015]). The histidine buffer comprised by Tang’s invention is present at 0.34% to about 2.04% by weight (see pg. 17, claim 10).
MPEP 2144.05(I) also states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. In the instant case, the claimed buffer in the range of 4-6% does not overlap with Tang’s composition comprising 0.34% to about 2.04% by weight of buffer, but it is merely close. Since Tang establishes the functions and properties relative to the buffer and its percentage by weight present in the lyophilized therapeutic protein composition (i.e., lyophilized cake); the instantly claimed composition comprising a buffer in the range of 4-6% would have been suggested to one skilled in the art.
With respect to wherein the lyophilized composition maintains a pH value of 6-8 with osmolality in the range of 250-500 mOsm/Kg over a period of at least 12 months:
Tang teaches that the pre-lyophilized aqueous solution, as well as the reconstituted lyophilized liquid formulation, has a pH that assists in the maintenance of protein structure and function (see pg. 4, para[0037]); and that the liquid pre-lyophilized and post-reconstituted liquid formulations have a pH of about 6.0 ± 2 (see pg. 4, para[0037]). Furthermore, Tang teaches that one of the advantages of providing the lyophilized form of the protein, includes maintaining the stability of the protein over time, especially for at least 18 months at room temperature (see pg. 10, para[0092]). As such, Tang’s teachings read on the instantly claimed composition wherein the lyophilized composition maintains a pH value of 6-8 over a period of at least 12 months, as recited in claim 1.
With respect to the osmolality in the range of 250-500 mOsm/Kg: MPEP 2112.01(I) states that [w]here the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not inherently possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.
In the instant case, the teachings of Tang read on the claim limitations recited in instant claim 1 (i.e., pegaspargase in a range of 6-14%, a cryoprotectant in the range of 32-41%, an amino acid bulking agent in the range of 38-50%, and a buffer in the range of 4-6%), because Tang’s lyophilized cake comprises protein from about 6% to about 19%, stabilizers selected from a polyol, a sugar, an amino acid and combinations thereof present from about 19% to about 83%, a buffer present at 0.34% to about 2.04%. Therefore, the claimed properties and functions (i.e., osmolality in the range of 250-500 mOsm/Kg) of the instantly claimed composition and Tang’s lyophilized cake are presumed to be inherent. In other words, since Tang’s product (i.e., lyophilized therapeutic protein compositions/lyophilized cake) reads on the instantly claimed storage stable lyophilized composition; Tang’s product necessarily possesses the physicochemical property of osmolality in the range of 250-500 mOsm/Kg.
However, Tang does not expressly teach or suggest a wherein the lyophilized composition is substantially free of salt, and wherein a weight ratio of the amino acid bulking agent to the cryoprotectant is from 0.9 to 1.5, as recited in instant claim 1.
Wang’s article reviews four topics related to the lyophilization and development of solid protein pharmaceuticals, in particular cryo- and lyo-protection of proteins by excipients (see pg. 1, abstract). Wang teaches that certain salts can be used to stabilized solid proteins; however, the presence of uncrystallized salts in a freeze-concentrate usually depresses T’g, so the salt content in the protein formulations should be kept to a minimum (Franks, 1990)(see pg. 47, left column, paragraph 2). Additionally, that high levels of buffers or salts should be avoided because this may lead to potential pH changes during freezing and likely depression in T’g and Tg of dried formulations (Pikal, 1990b) (see pg. 48, left column, second to last paragraph).
Wang adds that factors such as the nature of salt, the salt concentration and cooling fate may also affect the extent of salt crystallization (see pg. 47, left column, paragraph 2).
Wang includes that Chang and Randall (1992) classified salts into three types based on their glass-forming tendency at a given cooling rate and subsequent thermal history:
(1) crystallizing salts such as maleic acid, Na2HPO4, Na2SO4, Na2CO3, KCl, and (NH4)2SO4;
(2) partially crystallizing (doubly unstable glass) salts such as NaCl, NaHCO3, K2HPO4, KH2PO4, CaCl2, MgCl2, glycine, and ß-alanine; and
(3) glass-forming salts such as NaH2PO4, sodium/potassium citrate, citric acid, histidine, and sodium/potassium acetate (see pg. 47, left column, second paragraph).
Wang also teaches that since glass-forming excipients can inhibit salt crystallization, salts can be potential protein stabilizers in the presence of other amorphous excipients (Hatley and Franks, 1991) (see pg. 47, left column, second paragraph).
Thus, the teachings of Tang, when combined with the teachings of Wang are suggestive of the claimed storage stable lyophilized composition wherein the lyophilized composition is substantially free of salt as recited in instant claim 1. Tang’s stable lyophilized therapeutic protein compositions comprise a stabilizer (i.e., sugars and amino acids) and a buffer (i.e., histidine buffer) and as previously discussed, disaccharides such trehalose and sucrose, either alone or in combination with an amino acid, tend to form an amorphous glass during lyophilization. Since glass-forming excipients (e.g., trehalose and sucrose) can inhibit salt crystallization, the presence of histidine buffer (e.g., a glass-forming salt) potentiates the stability of the protein in the lyophilized composition. Thus, resulting in a lyophilized composition substantially free of salt.
Additionally, Wang also discusses the selection of a bulking agent(s) in relation to the lyophilized product (see pg. 45, right column, 2nd to last paragraph). For instance Wang teaches that crystallizing bulking agent(s) is usually needed in a solid protein formulation to have one or more of the following functions: to provide mechanical support of the final cake, to improve product elegance, to improve formulation dissolution, and to prevent product collapse and blowout (see pg. 45, right column, 2nd to last paragraph). A bulking agent(s) should have enough solubility, compatibility with the protein, no or minimal toxicity, and high eutectic temperature, allowing efficient freeze-drying (see pg. 45, right column, 2nd to last paragraph). Also that different bulking agents may affect stability of solid proteins to different degrees, for instance among mannitol, glycine or alanine, glycine was apparently best in protecting protein stability (see pg. 47, right column, last paragraph and pg. 48, left column, 1st paragraph).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow the teachings of Tang in order to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to do so because it was known that lyoprotectants (a.k.a stabilizers) are often included in pre-lyophilization formulations to protect the protein against denaturation during the freeze-drying process; because it was known that sugars are used as stabilizers/bulking agents, amino acids are used as stabilizers and glycine is a commonly used bulking agent and stabilizer; and because it was known that histidine buffer included in the pre-lyophilization aqueous protein solution is capable of effectively buffering between pH 4.8 and 7.2 and of stabilizing the protein before lyophilization and after reconstitution as taught by Tang.
One of ordinary skill in the art would have had a reasonable expectation of success given that glass-forming excipients (e.g., disaccharides such as trehalose and sucrose) can inhibit salt crystallization, thus salts (e.g., histidine buffer) can be potential protein stabilizers in the presence of other amorphous excipients; given that high levels of buffers or salts should be avoided because this may lead to potential pH changes during freezing and likely depression in T’g and Tg of dried formulations; and given that the salt content in protein formulations should be kept to a minimum as taught by Wang. Therefore, Tang’s stable lyophilized therapeutic protein compositions support the instantly claimed storage stable lyophilized composition wherein the lyophilized composition is substantially free of salt, by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the use of known technique to improve similar devices (methods, or products) in the same way and/or the application of a known technique to a known device (method, or product) ready for improvement to yield predictable results pursuant to KSR.
With respect to wherein a weight ratio of the amino acid bulking agent to the cryoprotectant is from 0.9 to 1.5:
As previously mentioned, Tang teaches that a stabilizer is a combination of chemical entities (i.e., more than one chemical entity) that together serve to stabilize the protein or other macromolecule (see pg. 2, para[0017]). Tang also teaches that a larger molecular weight chemical entity, such as e.g., sucrose or trehalose, is paired with a smaller molecular weight chemical entity, such as e.g., glycine and that the smaller chemical entity increases mobility, enabling the protein to relax to a lower energy state (see pg. 2, para[0017]).
Wang teaches that the presence of a bulking agent may affect properties of an amorphous excipient (see pg. 47, right column, last paragraph). The T’g and Tg of a mixture of sucrose and glycine decreased with increasing amino acid : sucrose ratio (Lueckel et al., 1998a) (see pg. 47, right column, last paragraph). Thus to keep T’g at a level enough for efficient lyophilization, the relative quantity of a bulking agent should be properly chosen and optimized (see pg. 48, left column, first paragraph).
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 ratio of the amino acid bulking agent to the cryoprotectant needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the ratio of stabilizer (i.e., amino acid:sugar) taught by Tang, because an ordinary skilled artisan would have been able to utilize the teachings of Wang to obtain various weight ratio parameters of bulking agent with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the amino acid bulking agent to cryoprotectant in the composition would have been obvious at the time of Applicants’ invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Regarding claim 5, Tang’s lyophilized cake comprises a stabilizer selected from the group consisting of a polyol, a sugar, an amino acid (see pg. 17, claim 12); thereby corresponding to wherein the cryoprotectant is selected from the group consisting of sugar, polyol, polymer, and amino acid, as recited in instant claim 5.
Regarding claim 7, Tang’s lyophilized cake further comprises a buffer, wherein said buffer is selected from the group consisting of citrate, phosphate, histidine, succinate, carbonate acetate, and a combination thereof (see pg. 18, claim 52). Thereby constituting wherein the buffer is selected from the group consisting of phosphate buffer, sodium phosphate buffer, potassium phosphate buffer, TRIS, and citrate buffer, as recited in instant claim 7.
3. Claims 2-3 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over US2018/0099049 A1 Pub. Date: Apr. 12, 2018 (herein after “Tang”) as evidenced by Kozlowski et al. BioDrugs 2001; 15(7): 419-429 (herein after “Kozlowski”) in view of Wang. W., International Journal of Pharmaceutics 203 (2000) 1-60 (herein after “Wang”) as applied to claim 1 above, and further in view of WO2018/017190 A2, published on January 25th 2018 (Cited in the IDS filed on 06/16/2021) (hereinafter “Fornasini”), and US2012/0100121A1, published on April 26th 2012 (hereinafter “Abribat”),
as applied to claims 2-3 and 17-19 herewith.
Regarding claim 1, see discussion of Tang and Wang above.
Regarding claims 2 and 18, Tang does not expressly teach compositions comprising pegaspergase.
Fornasini teaches a lyophilized storage stable composition (see Fornasini, Abstract), which includes a polyalkylene oxide-asparaginase and one or more of a buffer, a salt, and a sugar (see Fornasini, Abstract). The compositions find use in a variety of applications, e.g., in the treatment of a neoplastic condition in a subject (see Fornasini, Abstract). The composition includes a polyalkylene oxide group covalently linked by a linker to an asparaginase (see Fornasini, pg. 7, lines 12-14), thereby constituting a polyalkylene oxide group covalently linked by a linker to asparaginase as recited in instant claim 2. Asparaginase is an enzyme that may be composed of four identical subunits with one active site per tetramer (see Fornasini, pg. 7, lines 19-20). For example, the asparaginase enzyme can be L-asparaginase (see Fornasini, pg. 7, lines 20-21), thereby constituting L-asparaginase as recited in instant claim 2. Fornasini goes on to teach that the polyalkylene oxide is a polyethylene glycol (PEG) (see Fornasini, pg. 11, line 8), and in some instances the polyethylene glycol is a methoxypolyethylene glycol (e.g., monomethoxypolyethylene glycol, or "mPEG") (see Fornasini, pg. 11, lines 19-20), thereby constituting wherein the polyalkylene oxide is a mono-methoxy polyethylene glycol (mPEG) as recited in instant claim 2. As such, the polyalkylene oxide group may be covalently attached to the asparaginase through the linker (see Fornasini, pg. 11, lines 23-24). The linker may be any convenient functional group that allows for attachment of the polyalkylene oxide group to the asparaginase (see Fornasini, pg. 11, lines 24-25), such as, but not limited to, a urethane linker (also known as a carbamate linker), a succinate linker, and the like (see Fornasini, pg. 12, lines 6-7). Fornasini teaches a chemical reaction (see Fornasini, top of pg. 13) where methoxypolyethylene glycol succinimidyl succinate (also referred to as SS-PEG) is reacted with an amino group of an amino acid of a polypeptide (e.g., asparaginase) to produce a polyethylene glycol-asparaginase with a succinate linker (see Fornasini, pg. 13, lines 3-5), thereby constituting where the pegaspargase is a pegylated asparaginase consisting of a polyalkylene oxide group (mPEG) covalently linked by a succinate linker to asparaginase as recited in instant claim 2.
Abribat’s invention is drawn to a conjugate of a protein having substantial L-asparagine aminohydrolase activity and polyethylene glycol (see Abribat, front pg., abstract). Abribat adds that the invention also includes a pharmaceutical composition comprising the protein conjugate in a vial as a lyophilized powder to be reconstituted with a solvent (see Abribat, pg. 11, para[0129]). Abribat also teaches that in order to couple PEG to a protein, the PEG has to be activated at its OH terminus (see Abribat, pg. 2, para[0014]). The activation group is chosen based on the available reactive group on the protein that will be PEGylated (see Abribat, pg. 2, para[0014]). In the case of proteins, the most important amino acids are lysine, cysteine, glutamic acid, aspartic acid, C-terminal carboxylic acid and the N-terminal amino group (see Abribat, pg. 2, para[0014]). In view of the wide range of reactive groups in a protein nearly the entire peptide chemistry has been applied to activate the PEG moiety (see Abribat, pg. 2, para[0014]). Examples for this activated PEG-reagents are activated carbonates, e.g., p-nitrophenyl carbonate, succinimidyl carbonate; active esters, e.g., succinimidyl ester; and for site specific coupling aldehydes and maleimides have been developed (see Abribat, pg. 2, para[0014]). Furthermore, Abribat teaches a conjugate of a protein having substantial L-asparagine aminohydrolase activity and polyethylene glycol (see Abribat, pg. 2, para[0017]). In one embodiment, the PEG is covalently linked to one or more amino groups (wherein "amino groups" includes lysine residues and/or the N-terminus) of the L-asparaginase (see Abribat, pg. 2, para[0019]). In a more specific embodiment, the PEG is covalently linked to the one or more amino groups by an amide bond (see Abribat, pg. 2, para[0019]), thereby constituting wherein the mPEG is covalently linked via an amide bond as recited in instant claim 2.
The number of PEG moieties which can be coupled to the protein will be subject to the number of free amino groups and, even more so, to which amino groups are accessible for a PEGylation reaction (see Abribat, pg. 6, para[0074]). In a particular embodiment, the degree of PEGylation (i.e., the number of PEG moieties coupled to amino groups on the L-asparaginase) is within a range from about 10% to about 100% of free and/or accessible amino groups (see Abribat, pg. 6, para[0074]). Abribat teaches that the conjugate of the invention can be represented by the formula Asp-[NH-CO-(CH2)x-CO-NH-PEG]n wherein Asp is a L-asparaginase protein, NH is the NH group of a lysine residue and/or the N-terminus of the protein chain, PEG is a polyethylene glycol moiety and n is a number of at least 40% to about 100% of the accessible amino groups ( e.g., lysine residues and/or the N-terminus) in the Asp, and x is an integer ranging from 1 to 8, more specifically from about 2 to 5 (see Abribat, pg. 3, para[0019]). In a specific embodiment, the PEG is monomethoxy-polyethylene glycol (mPEG) (see Abribat, pg. 3, para[0019]). In one embodiment, the conjugate comprises a ratio of mol PEG/mol monomer of about 4.5 to about 8.5, particularly about 6.5 (see Abribat, pg. 8, para[0096]). In one embodiment, the conjugate comprises a ratio of mol PEG/mol monomer of about 12.0 to about 18.0, particularly about 15.1 (see Abribat, pg. 8, para[0097]), thereby constituting where the mPEG is covalently linked by a succinate linker via an amide bond to one or more primary amine groups of an L-asparaginase through conjugation, where conjugation results in covalent attachment of 1-12 mPEG per monomer of L-asparaginase as recited in instant claim 2.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Tang’s lyophilized therapeutic protein composition and Fornasini’s lyophilized storage stable composition comprising polyalkylene oxide-asparaginase in order to arrive at the instantly claimed invention.
One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because when methoxypolyethylene glycol succinimidyl succinate (also referred to as SS-PEG) is reacted with an amino group of an amino acid of asparaginase it is known to produce polyethylene glycol asparaginase as taught by Fornasini; because the degree of pegylation or mPEG moieties that covalently link to one or more amino groups by an amide bond was also known to range between about 12.0 to about 18.0 mol PEG/mol monomer and the conjugate comprising L-asparaginase and polyethylene glycol was known to exhibit aminohydrolase activity as taught by Abribat. And because Abribat’s pharmaceutical composition comprising a conjugate of a protein having substantial L-asparagine aminohydrolase activity and PEG was lyophilized and stored in a vial, to be reconstituted with a solvent.
One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that lyophilized storage stable compositions comprising polyalkylene oxide-asparaginase wherein the polyalkylene oxide is a polyethylene glycol (PEG) and in some instances methoxypolyethylene glycol (mPEG) find use in a variety of applications including neoplastic conditions as taught by Fornasini; and given that lyophilized therapeutic protein compositions as taught by Tang encompass therapeutic proteins such as pegaspargase (i.e., PEG-protein conjugate/ PEGylated asparaginase) as evidenced by Kozlowski. Therefore, combining the teachings of Tang and Fornasini would support the instantly claimed composition as recited in instant claim 2, by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention; and/or the combination of prior art elements according to known methods to yield predictable results, pursuant to KSR.
Regarding claim 3, Abribat teaches a conjugate comprising an L-asparaginase from Erwinia (see Abribat, pg. 18, claim 1). See also Fig. 1, which displays the SDS-polyacrylamide gel electrophoresis of purified recombinant Erwinia chrysanthemi L-asparaginase (see Abribat, pg. 3, para[0023]). Thereby constituting wherein L-asparaginase is from a bacterial source selected from the group consisting of E. coli, and Erwinia chrysanthemi, and genetically engineered E. coli, as recited in instant claim 3.
Regarding claim 17, Tang does not expressly teach or suggest wherein the final concentration of pegaspargase is in the range of 750 ± 20% IU/ml when the composition is reconstituted post lyophilization to a volume per vial of 1-5.5 mL.
Fornasini teaches a lyophilized storage stable composition (see Fornasini, Abstract), and that the lyophilized composition powder for injection was produced in a single-use vial containing 3,750 IU of active PEGylated L-asparaginase (750 IU/mL after reconstitution with 5.2 mL of water for injection (WFI)) (see Fornasini, pg. 65, lines 3-5), thereby constituting wherein the final concentration of pegaspargase is in the range of 750 +/- 20% IU/mL in a volume of 5.5mL as recited in instant claim 17.
Regarding claim 19, Tang teaches that the lyophilized cake comprises sucrose, wherein the sucrose is present at about 15 % to about 71 % by weight (see pg. 17, claim 12). Thereby constituting wherein the sugar includes sucrose, as recited in instant claim 19.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 U.S.C 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references discussed above.
Response to Arguments
Applicants' arguments filed 01/28/2026 with respect to the 35 U.S.C. 103 rejection, have been fully considered and are persuasive.
However, in response to Applicants’ argument that (B) The storage stable lyophilized composition of independent claim 1 provides beneficial and unexpected results that are not contemplated by the combination of the cited references (see Remarks, filed 01/28/2026, pg. 8 of 16), have been considered but are not persuasive.
Applicants’ assertions are not persuasive because: Pursuant to MPEP 716.02(c)(II), expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
As discussed in the 35 U.S.C 103 rejection, Tang’s teachings read on the instantly claimed storage stable lyophilized composition, because Tang’s lyophilized cake comprises a protein present from about 6% to about 19% weight; a stabilizer present from about 19 to about 83% weight, wherein the stabilizer is a combination of an amino acid (i.e., glycine) and a sugar (i.e., sucrose present at about 15% to about 71% by weight), and a buffer (i.e., histidine buffer) present at 0.34% to about 2.04% by weight. Tang also discusses details pertaining to the buffer and protein stability, and how the chosen buffer should be one capable of maintaining protein stability and pH pre-lyophilization and after reconstitution.
Wang teaches the importance of selecting the appropriate bulking agents and stabilizers in relation to the protein stability and final lyophilized product. For instance, Wang discusses salts as stabilizers in the presence of amorphous excipients as well as the optimization of the ratio of bulking agents to stabilizer for efficient lyophilization. Wang also teaches that crystallizing bulking agent(s) is usually needed in a solid protein formulation to have one or more of the following functions: to provide mechanical support of the final cake, to improve product elegance, to improve formulation dissolution, and to prevent product collapse and blowout. A bulking agent(s) should have enough solubility, compatibility with the protein, no or minimal toxicity, and high eutectic temperature, allowing efficient freeze-drying. Wang also discusses buffers and advices on avoiding high levels of buffers or salts which may lead to potential pH changes during freezing and likely depression in the glass transition temperature.
Since the instantly claimed composition comprises sucrose as a cryoprotectant and glycine as the amino acid bulking agent, and a buffer in the range of 4-6%; and since the effects of sucrose, glycine, and high levels of buffers or salts in relation to lyophilized compositions are well known in the art, as discussed above in the 35 U.S.C 103 rejection. Thus, the beneficial and unexpected results obtained by Applicants are in fact expected. Accordingly, Applicants’ arguments are not persuasive and obviousness rejection of claims 1-3, 5, 7 and 17-19 has been maintained.
Conclusion
No claims are allowed.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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