DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 30, 2025, has been entered.
Claims 1-152 and 158 are canceled.
Claims 153-157 and 159-170 are pending. Claims 162-169 are withdrawn.
Claims 153-157, 159-161, and 170 are examined on the merits.
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.
Claims 153-157, 159-161, and 170 are 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.
The term “substantially the same” in claims 153 and 161 is a relative term which renders the claims indefinite. The term “substantially the same” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what similarity in asparaginase activity (e.g., 70% activity retained, 99% activity retained, etc.) is required for an asparaginase activity of the polyalkylene oxide-asparaginase after the storage period to be considered “substantially the same” as an asparaginase activity of the polyalkylene oxide-asparaginase before the storage period. The specification gives examples of retention of activity (e.g., page 14, lines 28-31), but does not limit the scope. Since claim 153 is indefinite, then the claims that incorporate it, claims 154-157, 159, 160, and 170, are rendered indefinite. Thus, claims 153-157, 159-161, and 170 are rejected under 35 U.S.C. 112(b).
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.
Claims 153-157, 159-161, and 170 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.
The following limitation of claims 153 and 161 is not supported by the specification as filed: “the composition remains stable when stored at 2-8 ºC for at least 30 months, such that an asparaginase activity of the polyalkylene oxide-asparaginase after the storage period is substantially the same as an asparaginase activity of the polyalkylene oxide-asparaginase before the storage period.” The specification states that “In some cases, a storage stable composition substantially retains its activity over an extended period of time…” (page 14, lines 28-29), with respect to a lyophilized composition. It is further disclosed that “An extended period of time is a period of time such as 1 week or more…or 2.5 years (e.g., 30 months) or more, or 3 years or more, or 3.5 years (e.g., 42 months) or more, or 4 years or more, or 4.5 years (e.g., 54 months) or more, or 5 years or more” (page 15, lines 8-13). Also, it is stated that “In some instances, a storage stable composition is substantially stable for an extended period of time at a temperature less than ambient temperature, such as a temperature of…2 to 8ºC” (page 15, lines 23-25). However, when disclosing the composition as substantially stable at 2 to 8ºC (page 15, lines 23-25), the specification does not disclose that the extended period of time is specifically the embodiment of 30 months or more, i.e. at least 30 months. Moreover, when discussing “stable,” “storage stable,” and “substantially stable” compositions on pages 14-15 of the specification, the discussion is with respect to a lyophilized composition, not a liquid composition as claimed (page 14, lines 13-21).
Additionally, the specification discloses studies in Example 1 that do not provide support for the claimed limitation. First, Example 1 discloses a study in which a bulk drug substance composition that included a polyethylene glycol-asparaginase for lyophilization is held at 2-8ºC for up to 2 months prior to lyophilization (page 62, lines 4-6). The bulk drug substance is directed to a liquid composition (see Tables 3-5, disclosing a colorless solution). The concentrated bulk drug substance material was studied at 0, 2, 4, 6, 8, and 12 weeks at 2-8ºC, and stability samples were maintained in sample bags with product contact surface of polyethylene (page 62, lines 24-26). The maximum time period of 12 weeks is a period of 3 months. Tables 3-5 show stability data for two lots stored at 2-8ºC (pages 63-65). Though stability was tested for a liquid composition at the claimed storage temperature range, the data does not speak to the stability for any period in the claimed range of “at least 30 months,” which is a range that does not include an upper limit, thereby including significantly long periods of time such as 100 years.
In another study discussed in Example 1 of the specification, a lyophilized polyethylene glycol-asparaginase formulation was developed to attain a stable lyophilized composition that was suitable for 2-8ºC for at least 18 months (page 65, lines 15-17). However, that study is not directed to a liquid composition as claimed.
Also, Example 1 includes a study of long-term stability at 2-8ºC (pages 73-76). However, that study is also directed to the stability of a lyophilized composition, rather than the stability of a liquid composition as claimed.
While Applicant was in possession of a portion of the claimed invention, the full scope of the claimed invention, specifically a liquid composition that remains stable when stored at 2-8ºC for at least 30 months, such that an asparaginase activity of the polyalkylene oxide-asparaginase after the storage period is substantially the same as an asparaginase activity of the polyalkylene oxide-asparaginase before the storage period, is not fully described in the specification. As such, Applicant was not in possession of the full scope of the claimed invention at the time of filing. Because the specification as filed fails to provide clear support for the new claim language, a new matter rejection is clearly proper.
Notice Re: Prior Art Available Under Pre-AIA and AIA
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 153-157, 159-161, and 170 are rejected under 35 U.S.C. 103 as being unpatentable over Soares (International Journal of Pharmaceutics. 2002. 237: 163-170. Listed on IDS filed 12/12/23) in view of Oncaspar (Prescribing Information. Sigma-tau Pharmaceuticals, Inc. March 2011. Listed on IDS filed 12/12/23), Angiolillo (Journal of Clinical Oncology. 2014. 32(34): 3874-3882. Listed on IDS filed 12/12/23), and Zalipsky (Chapter 10. in: Dunn, RL et al., Polymeric Drugs and Drug Delivery Systems (Washington DC, American Chemical Society, 1991), pp. 91-100. Previously cited).
Soares discloses a study investigating PEG-L-asparaginase stability and activity changes in different solutions and buffers with respect to the variations of pH, temperature, and human serum reactivity (page 164, right column, last full paragraph). Additionally, in attempting to improve PEG-L-asparaginase shelf-life, Soares studied the stability of the modified enzyme during lyophilization (page 164, right column, last full paragraph). PEG (polyethylene glycol) is a polyalkylene oxide (for instance, see page 9, lines 15-22 of the instant specification). To obtain the PEG-L-asparaginase, L-asparaginase was combined with activated PEG (page 165, right column, second full paragraph). In this reaction, PEG is conjugated to L-asparaginase (abstract), in which activated PEG binds to the free amino acid group situated in the amino acid side chains of the protein (in this case, L-asparaginase) (page 164, left column, last full paragraph). Therefore, PEG-L-asparaginase meets the claimed ‘polyalkylene oxide-asparaginase,’ wherein ‘the polyalkylene oxide-asparaginase comprises an asparaginase covalently linked to a polyalkylene oxide group which is a polyethylene glycol’ as required by instant claim 153.
Section 2.7 of Soares, directed to a freeze-drying experiment, teaches a composition that meets limitations of the liquid composition of instant claim 153 and 161, and a kit meeting limitations of the kit of instant claim 170. See page 166, left column, first paragraph. In particular, aliquots of PEG-L-asparaginase (0.03 IU/µL) solution in phosphate buffer pH 7.3 were prepared containing 1.2 mg/ml NaH2PO4 (i.e. monobasic sodium phosphate - see page 18, lines 7-8 of the instant specification), 5.6 mg/ml Na2HPO4 (i.e. dibasic sodium phosphate – see page 18, lines 6-7 of the instant specification), and 8.5 mg/ml NaCl (i.e. sodium chloride). The aliquots are directed to a liquid composition consisting of PEG-L-asparaginase, dibasic sodium phosphate, monobasic sodium phosphate, and sodium chloride. For those aliquots, the concentration of NaCl is calculated below to be 0.85 wt% NaCl, 0.56 wt.% Na2HPO4 (dibasic sodium phosphate), and 0.12 wt.% NaH2PO4 (monobasic sodium phosphate), based on approximating the density of the aliquots to the density of water (i.e. 1 g/mL).
Calculations:
[Wingdings font/0xE0] salt:
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A liquid aliquot of Soares meets limitations of the claimed liquid composition, wherein the concentration of dibasic sodium phosphate (0.56 wt.%) falls in the range of instant claim 153 and is very close to the concentration of instant claim 161 thus rendering it obvious (a prima facie case of obviousness exists where the claimed amount does not overlap with the prior art but are merely close; see MPEP 2144.05(I)), the concentration of monobasic sodium phosphate (0.12 wt.%) falls in the range of instant claim 153 and is the concentration of instant claim 161, the concentration of sodium chloride (0.85 wt%) falls in the range of instant claim 153 and is the concentration of instant claim 161. The aliquots were frozen in freeze-drier vials using an FTS Systems freeze-drier (see also page 165, last paragraph for teaching of freeze-drier vials). The vials comprising the aliquots prior to freeze drying is directed to kit comprising one or more unit dosage containers (each vial is directed to a unit dosage container) each containing a liquid composition (a liquid aliquot), thereby meeting limitations of instant claim 170.
In sum, the aliquots of PEG L-asparaginase solution in the phosphate buffer of Soares meet limitations of instant claims 153 and 161 since they are directed to a liquid composition consisting of:
a polyalkylene oxide-asparaginase (PEG-L-asparaginase);
dibasic sodium phosphate at a concentration of 0.56 wt.% (see calculation above);
monobasic sodium phosphate at a concentration of 0.12 wt.% (see calculation above); and
sodium chloride at a concentration of 0.85 wt.% (see calculation above),
wherein the polyalkylene oxide-asparaginase comprises an asparaginase covalently linked to a polyalkylene oxide group that is a polyethylene glycol.
Soares differs from the claimed invention in that Soares does not expressly disclose the following:
The concentration of the polyalkylene oxide-asparaginase (PEG-L-asparaginase) is 750 IU per ml of the liquid composition; Instead, Soares discloses a concentration of 0.03 IU/µl (page 166, left column, first paragraph) which converts to 30 IU per mL of the composition according to the following calculation:
0.03
I
U
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10
3
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30
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The polyalkylene oxide group (a polyethylene glycol) is covalently linked by a carbamate moiety to the asparaginase, wherein the carbamate moiety is derived from a succinimidyl carbonate (SC) linker.
The liquid composition (the aliquot) remains stable when stored at 2-8ºC for at least 30 months, such that an asparaginase activity of the polyalkylene oxide-asparaginase after the storage period is substantially the same (the Examiner is interpreting ‘substantially the same’ as any extent of similarity) as an asparaginase activity of the polyalkylene oxide-asparaginase before the storage period.
Regarding difference (i) (Soares does not expressly disclose the PEG-L-asparaginase at a
concentration of 750 IU per mL of the liquid composition):
Oncaspar discloses the Oncaspar product which is useful for the treatment of acute lymphoblastic leukemia (page 1, Indications and Usage section). Oncaspar is supplied as a preservative-free, isotonic sterile solution in phosphate-buffered saline, pH 7.3, wherein each milliliter contains 750 ± 150 IU of pegaspargase (i.e. L-asparaginase that is covalently conjugated to monomethoxypolyethylene glycol (mPEG)), 5.58 mg dibasic sodium phosphate, 1.20 mg monobasic sodium phosphate, and 8.50 mg sodium chloride in water for injection (page 4, Section 11). The concentration of 5.58 mg/mL dibasic sodium phosphate is very close to the concentration of 5.6 mg/mL in the liquid aliquots of Soares, and the concentrations of the monobasic sodium phosphate and sodium chloride (1.20 mg/mL and 8.50 mg/mL, respectively) are the same as those in the liquid aliquots of Soares (see page 166, left column, first paragraph of Soares).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have varied the enzymatic activity of the L-asparaginase that is conjugated to PEG in Soares, including using an L-asparaginase such that the PEG-L-asparaginase solution has an activity higher than 30 IU/mL taught in Soares (see calculation above regarding Soares), including 750 IU/mL of the liquid composition (a liquid aliquot) of Soares. It would have been a matter of routine experimentation to have varied the enzymatic activity of the L-asparaginase that is used in the invention of Soares, particularly since Soares teaches that L-asparaginase is widely used in leukemia treatment (abstract) and thus the enzymatic activity would have been critical for adjusting dosages of the composition of Soares for the purpose of treating leukemia.
Additionally, one of ordinary skill in the art would have been motivated to have included the PEG-L-asparaginase at 750 IU/mL in the liquid aliquot of Soares because Oncaspar discloses including PEG-L-asparaginase in an amount of 750 ± 150 IU/mL in a liquid product that is useful for treating acute lymphoblastic leukemia; the treatment of leukemia as an effect of the L-asparaginase is sought by Soares (abstract). Since that activity level is taught in a commercially available product for the treatment of leukemia (Oncaspar), then the skilled artisan would have expected it to be suitable for the liquid composition of Soares for the purpose of treating leukemia. Since the composition of Oncaspar comprises concentrations of dibasic sodium phosphate, monobasic sodium phosphate, and sodium chloride that are the same or nearly identical to the concentrations of those components in the aliquots of Soares, then there would have been a reasonable expectation of obtaining an active product by modifying the concentration of the PEG-L-asparaginase in the Soares composition to the concentration used in Oncaspar.
Regarding difference (ii) (Soares does not expressly disclose that the
polyalkylene oxide group (a polyethylene glycol) is covalently linked by a carbamate moiety to the asparaginase, wherein the carbamate moiety is derived from a succinimidyl carbonate (SC) linker):
Angiolillo discusses asparaginase, indicating that it is a critical agent in the treatment of acute lymphoblastic leukemia (ALL) (page 3874, first paragraph). Angiolillo recognizes pegaspargase (SS-PEG) as a pegylated version of E. coli L-asparaginase that is a major component of acute lymphoblastic leukemia treatment, and was the first-line asparaginase preparation used in Children’s Oncology Group ALL trials (page 3874, first paragraph). Angiolillo also speaks of calaspargase pegol (SC-PEG) which is a pegylated asparaginase that uses the identical enzyme and polyethylene glycol moiety present in SS-PEG, but uses a succinimidyl carbonate linker that is more stable than the SS-PEG succinimidyl succinate linker (page 3874, second paragraph). The more stable succinimidyl carbonate (SC) linker also imparts improved drug product shelf life compared with SS-PEG (page 3880, first paragraph). Preclinical studies found that SC-PEG and SS-PEG have comparable pharmacokinetic and pharmacodynamic properties (page 3874, second paragraph). Angiolillo’s study determined the pharmacokinetic and pharmacodynamic comparability of SC-PEG and SS-PEG in patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (Purpose section in Abstract; page 3875, first paragraph). Angiolillo found that the mean half-life of plasma asparaginase activity for both SC-PEG doses tested was approximately 2.5 times longer than that of the SS-PEG dose tested (SS-PEG2500) (Results section in Abstract). The longer half-life of SC-PEG resulted in prolonged suppression of plasma asparagine (page 3878, right column, third paragraph).
Zalipsky teaches functionalized derivatives of polyethylene glycol (PEG) as reagents for preparation of PEG-protein conjugates (abstract). These reagents include methoxypoly(ethylene glycol)-N-succinimidyl carbonate (SC-PEG) (page 92, fifth paragraph). Zalipsky discloses subjecting a variety of proteins, including asparaginase, to modifications with SC-PEG, finding that they yield conjugates with excellent preservation of biological/enzymatic activities (abstract; page 93, second-to-last paragraph pointing to Table II which lists asparaginase modified with SC-PEG (5000)). Scheme II on page 97 shows the use of SC-PEG for covalent attachment of the polymer to proteins. In particular, Scheme II shows that PEG-chains grafted onto the polypeptide backbone (of the protein, e.g. asparaginase) through carbamate (urethane) linkages (page 95, last paragraph). With respect to the modified asparaginase, Zalipsky found that asparaginase showed good preservation of activity, even after extensive modifications with SC-PEG (page 98, last paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to have substituted the PEG-L-asparaginase (formed by modifying L-asparaginase with activated methoxypolyethylene glycol 5000 (succinimidyl succinate)) with calaspargase pegol (SC-PEG) in the liquid aliquots rendered obvious by Soares. One of ordinary skill in the art would have been motivated to do this because Angiolillo teaches that calaspargase pegol (SC-PEG) has a longer half-life of plasma asparaginase activity than SS-PEG, i.e. an asparaginase has been modified with a succinimidyl succinate-activated PEG, which is directed to the PEG-L-asparaginase of Soares, thereby resulting in prolonged suppression of plasma asparagine in the treatment of acute lymphoblastic leukemia in patients; this prolonged suppression would have been desired by Soares for the use of their composition in treating leukemia (abstract of Soares). Additionally, one of ordinary skill in the art would have been motivated to make this substitution because the succinimidyl carbonate linker would have imparted an improved drug product shelf life to the aliquots of Soares as compared with the succinimidyl succinate linker of the PEG-L-asparaginase used in Soares given that Angiolillo indicates that a succinimidyl carbonate linker imparts improved drug product shelf life and is more stable than the succinimidyl succinate linker (page 3880, first paragraph; page 3874, second paragraph of Angiolillo) which is the linker between the PEG and L-asparaginase in Soares. Further still, one of ordinary skill in the art would have been motivated to make the substitution because Zalipsky found that asparaginase showed good preservation of activity after extensive modifications with SC-PEG (page 98, last paragraph). There would have been a reasonable expectation of obtaining liquid aliquots with active asparaginase by the substitution since calaspargase pegol (SC-PEG) and L-asparaginase pegylated with succinimidyl succinate linker (SS-PEG), which is directed to the PEG-L-asparaginase of Soares, have comparable pharmacokinetic and pharmacodynamic properties (page 3874, second paragraph of Angiolillo), and asparaginase modified with succinimidyl carbonate-activated PEG was found to have good preservation of activity (page 98, last paragraph of Zalipsky). In light of Scheme II of Zalipsky showing that PEG-chains graft onto the polypeptide backbone (of the protein) through carbamate (urethane) linkages, then calaspargase pegol (SC-PEG) comprises an asparaginase covalently linked to a polyalkylene oxide group (a polyethylene glycol), wherein the polyalkylene oxide group is covalently linked by a carbamate moiety to the asparaginase (the protein), wherein the carbamate moiety is derived from a succinimidyl carbamate (SC) linker).
Regarding difference (ii) (Soares does not expressly disclose that the aliquot (directed to
the ‘liquid composition) remains stable when stored at 2-8ºC for at least 30 months, such that an asparaginase activity of the polyalkylene oxide-asparaginase after the storage period is substantially the same (the Examiner is interpreting ‘substantially the same’ as any extent of similarity) as an asparaginase activity of the polyalkylene oxide-asparaginase before the storage period):
Since the invention rendered obvious by Soares in view of Oncaspar, Angiolillo, and Zalipsky renders obvious the claimed liquid composition, specifically a liquid composition consisting of the claimed components in the claimed concentrations, then the liquid composition rendered obvious by the references necessarily has the claimed stability property. As pointed out in MPEP 2112(I), “Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.” Because the liquid composition rendered obvious by the references includes calaspargase pegol, then it would have been expected to remain stable when stored at 2-8ºC for at least 30 months, such that an asparaginase activity of the polyalkylene oxide-asparaginase (calaspargase pegol) after the storage period is substantially the same (the Examiner is interpreting ‘substantially the same’ as any degree of similarity) as an asparaginase activity of the polyalkylene oxide-asparaginase (calaspargase pegol) before the storage period based on the teachings of Angiolillo and Zalipsky. In particular, Angiolillo discloses calaspargase pegol uses a succinimidyl carbonate linker that is more stable than the SS-PEG succinimidyl succinate linker (page 3874, second paragraph). Likewise, Zalipsky discloses that biological activities of enzymes modified with SC-PEG were preserved to a great extent (page 98, third paragraph), and that asparaginase showed good preservation of activity, even after extensive modifications with SC-PEG (page 98, last paragraph). Further still, Angiolillo teaches that the more stable succinimidyl carbonate (SC) linker also imparts improved drug product shelf life compared with SS-PEG (page 3880, first paragraph).
As such, Soares in view of Oncaspar, Angiolillo, and Zalipsky renders obvious instant claims 153, 161, and 170.
Regarding instant claims 154-157, Angiolillo teaches that calaspargase pegol (SC-PEG) uses the identical enzyme and polyethylene glycol moiety present in pegaspargase (SS-PEG) which has a succinimidyl succinate linker (page 3874, second paragraph), wherein the enzyme is E. coli L-asparaginase (page 3874, first paragraph). Therefore, the asparaginase of calaspargase pegol is L-asparaginase, signifying that Soares in view of Oncaspar, Angiolillo, and Zalipsky renders obvious instant claim 154. Soares uses activated methoxypolyethylene glycol 5000 (succinimidyl succinate) (paragraph bridging pages 164 and 165). The succinimidyl carbonate-activated PEG in Zalipsky used to modify asparaginase comprises methoxypolyethylene glycol of molecular weight 5000, i.e. SC-PEG (5000) (Table II on page 94; page 92, last paragraph). For the calaspargase pegol of the invention rendered obvious by Soares in view of Oncaspar, Angiolillo, and Zalipsky, it would have been obvious to the person of ordinary skill in the art to use methoxypolyethylene glycol 5000, i.e. methoxypolyethylene glycol of molecular weight 5,000 daltons, since it appears to be the polyethylene glycol moiety present in pegaspargase (SS-PEG) based on Soares, therefore being the polyethylene glycol moiety in calaspargase pegol, and since methoxypolyethylene glycol of molecular weight 5,000 daltons was used in Zalipsky to modify asparaginase with succinimidyl carbonate-activated PEG. Therefore, instant claims 155, 156 (since 5,000 daltons falls in the claimed range), and 157 are rendered obvious.
Regarding instant claims 159 and 160, Soares in view of Oncaspar, Angiolillo, and Zalipsky differs from the claimed inventions in that they do not expressly disclose that the polyalkylene-oxide-asparaginase (calaspargase pegol) has the claimed elimination half-life (10-20 days for instant claim 159; 14-18 days for instant claim 160). However, in Soares in which the PEG-L-asparaginase includes a succinimidyl succinate linker (thus directed to SS-PEG in Angiolillo), they found from Figure 3 that the pegylated L-asparaginase is much more stable in human serum compared to unmodified enzyme (page 168, first paragraph). Figure 3 of Soares shows nearly 100% activity at the longest time point tested of 60 minutes. From this figure, the skilled artisan would have expected an elimination half-life much longer than 60 minutes. Additionally, Angiolillo found that the mean half-life of plasma asparaginase activity for both SC-PEG doses tested was approximately 2.5 times longer than that of the SS-PEG dose tested (SS-PEG2500) (Results section in Abstract). Based on that teaching in Angiolillo, the person of ordinary skill in the art would have expected that the elimination half-life of calaspargase pegol has an even longer elimination half-life than the pegylated L-asparaginase used in Soares which is directed to SS-PEG in Angiolillo. Figure 2 of Angiolillo shows mean plasma asparaginase activity over time, in which two doses of SC-PEG in Figure 2A fall from about 1,200 mIU/mL to about 600 mIU/mL in about 10 days and 12 days (their half life). In Figure 2B of Angiolillo, the lower dose of SC-PEG falls from about 1,200 mIU/mL to about 600 mIU/mL in about 20 days (its half life), while the higher dose of SC-PEG falls from about 1,500 mIU/mL to about 750 mIU/mL in about 15 days (its half life). Given the data shown in Figure 2 of Angiolillo, a similar length of time would have been expected for the elimination half-life of the aliquots rendered obvious by Soares in view of Oncaspar, Angiolillo, and Zalipsky; about 10, 12, 15, and 20 days fall in the range of instant claim 159, and about 15 and 20 days fall in the range of instant claim 160. Furthermore, since Soares in view of Oncaspar, Angiolillo, and Zalipsky renders obvious the composition of instant claim 153, then their composition necessarily has the same elimination half-life as the claimed invention, since the pegylation of the asparaginase would have affected the stability of the asparaginase, and the concentration of the pegylated asparaginase and the other chemicals (and their concentrations) would have been expected to affect the stability and activity of the asparaginase. Therefore, instant claims 159 and 160 are rendered obvious.
Response to Arguments
Applicant’s arguments, filed June 30, 2025, with respect to the objections to claims 153-161 and 170, the rejection under 35 U.S.C. 112(a) of claims 153-161 and 170, and the rejection under 35 U.S.C. 103 of claim 158 as being unpatentable over Soares, Oncaspar, Angiolillo, and Zalipsky in further view of Hellman, have been fully considered and are persuasive. In particular, the objections have been overcome by the amendments to claims 153 and 161. The rejection under 35 U.S.C. 112(a) has been overcome by the amendments to claims 153 and 161. The rejection under 35 U.S.C. 103 over Soares, Oncaspar, Angiolillo and Zalipsky in further view of Hellman has been rendered moot by the cancelling of claim 158. Therefore, these objections and rejections have been withdrawn.
However, Applicant’s arguments are unpersuasive with respect to the rejection under 35 U.S.C. 103 of claims 153-157, 159-161, and 170 over Soares in view of Oncaspar, Angiolillo, and Zalipsky, which has been modified as necessitated by the amendments. Additionally, the amendments to the claims necessitated new grounds of rejection under 35 U.S.C. 112(b) and 112(a).
Regarding the rejection under 35 U.S.C. 103, Applicant highlights that the claims now include a stability limitation, requiring that the asparaginase activity remains stable for at least 30 months when stored at 2-8ºC. Applicant asserts that this amendment is based on the surprising discovery that the succinimidyl carbonate (SC) linker affords an exceptionally long stability of a liquid composition of asparaginase without altering its activity. Applicant asserts that there is nothing in the references cited by the Office to suggest that the claimed combination of ingredients and amounts would have exhibited the high degree of long-term stability presently claimed, especially in view of the consistent teachings in the cited references that formulating asparaginase (particularly without any stabilizing agents) is unpredictable due to protein denaturation and/or activity loss, citing as an example page 164 of Soares. The Examiner respectfully disagrees because Soares found that the PEG-asparaginase was stable at 8ºC for a longer period than one month when maintained in phosphate buffer of pH 7.3 (page 168, left column, first paragraph). This points to the cited art recognizing that PEG attachment to asparaginase stabilizes the enzyme when stored at a temperature (in this case, 8ºC) falling within the claimed range of 2-8ºC. Moreover, there would have been a reasonable expectation that the composition rendered obvious by the references remains stable when stored at 2-8ºC for a period of time longer than one month, including for a time period falling within the claimed range of “at least 30 months,” due to the substitution of the PEG-asparaginase of Soares with calaspargase pegol. This expectation is supported by the teachings regarding calaspargase pegol (SC-PEG) in Angiolillo, which states that it uses a succinimidyl carbonate linker that is more stable than the SS-PEG succinimidyl succinate linker (page 3874, second paragraph). See the new grounds of rejection addressing the new limitation.
Applicant also submits a declaration under 37 C.F.R. 1.132 by Dr. Alexandar Wright filed June 30, 2025. The Declaration (the Wright Declaration) is insufficient to overcome the rejection of claims 153-157, 159-161, and 170 based upon Soares in view of Oncaspar, Angiolillo, and Zalipsky applied under 35 U.S.C. 103 as set forth in the Office action. Specifically, Applicant asserts that the Wright Declaration offers evidence that asparaginase compositions that contain a succinimidyl carbonate (SC) linker yields several unexpected properties (including enhanced stability, longer half-life, improved manufacturing process and tighter product specification), thus thwarting any assumption that the prior art composition (e.g., the compositions of Soares and/or the liquid Oncaspar product label that do not contain the SC linker) would have similar properties. The Wright Declaration indicates that Asparlas® corresponds to the formulation identified in Table 25 of the instant application (paragraph 4 of declaration). The Examiner notes that the polyalkylene oxide-asparaginase of Asparlas®, i.e. the formulation in Table 25 of the specification, is calaspargase pegol. Paragraph 5 of the Wright Declaration states that due to the SC linker, Asparlas has a significantly longer shelf life (36 months) compared to liquid Oncaspar (8 months); the modified asparaginase of Asparlas has a longer half-life with an associated prolonged asparaginase activity and asparagine depletion that is maintained longer than liquid Oncaspar, and Asparlas is administered intravenously less frequently than liquid Oncaspar due to the longer half-life of Asparlas. However, the Examiner finds that these are not unexpected results based on the teachings of Angiolillo. In particular, Angiolillo teaches the polyalkylene oxide-asparaginase of Asparlas, calaspargase pegol, and points out that calaspargase pegol (SC-PEG) uses a succinimidyl carbonate linker that is more stable than the SS-PEG succinimidyl succinate linker (page 3874, second paragraph), which is the linker of Oncaspar. Angiolillo also teaches the more stable SC linker imparts improved drug product shelf life compared with SS-PEG (page 3880, first paragraph). Given these teachings in Angiolillo, then the longer shelf would have been expected by the skilled artisan for the liquid composition rendered obvious by the cited references which comprises calaspargase pegol.
Additionally, paragraph 6 of the Wright Declaration indicates that Asparlas has numerous other unexpected advantages compared to liquid Oncaspar, including an improved manufacturing process that is more amendable to process development and better product specification parameters. The comparison of the Asparlas manufacturing process with the liquid Oncaspar process is summarized in Figure 1 of the declaration, and the tighter final product specification differences between Asparlas and liquid Oncaspar is provided in Figure 2 of the declaration. However, the disclosure of borate buffer and the exclusion of sodium hydroxide (NaOH) for the manufacturing of Asparlas in Fig