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 .
The amendment filed April 27, 2026, has been received and entered.
Claims 1-152 and 158 are canceled. Claims 171 and 172 are new.
Claims 153-157 and 159-172 are pending. Claims 162-169 are withdrawn.
Claims 153-157, 159-161, and 170-172 are examined on the merits.
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.
Claims 153-157, 159-161, and 170-172 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 90% or more of an initial asparaginase activity of the polyalkylene oxide-asparaginase is retained during the storage period.” Likewise, the ranges of instant claims 171 and 172 (narrower ranges of asparaginase activity retention) are not supported by the specification. The specification states that “In some cases, a storage stable composition substantially retains its activity over an extended period of time, such as retains…90% or more…of its activity over an extended period of time” (page 14, line 28 through page 15, line 2), 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, or that “substantially stable” is the embodiment of retention of 90% or more of the initial asparaginase activity. 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, far less than the claimed time period of “at least 30 months.” Tables 3-5 show stability data for three 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. Moreover, the polyethylene glycol-asparaginase of Example 1 has an SS-PEG linker (page 59, lines 3-4 and 16-23), not a succinimidyl carbonate (SC) linker as claimed.
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 90% or more, 95% or more, or 98% or more, of an initial asparaginase activity of the polyalkylene oxide-asparaginase is retained during 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 170-172 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 concentrations of NaCl and the phosphate buffers are 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
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3
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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 90% or more (or 95% or more as in instant claim 171; or 98% or more as in instant claim 172) of an initial asparaginase activity of the polyalkylene oxide-asparaginase is retained during 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 (iii) (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 90% or more (or 95% or more as in instant claim 171; or 98% or more as in instant claim 172) of an initial asparaginase activity of the polyalkylene oxide-asparaginase is retained during 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 (the claimed asparaginase activity retention when stored at 2-8ºC for at least 30 months; i.e., the composition remains stable when stored at 2-8 ºC for at least 30 months, such that 90% or more, 95% or more, or 98% or more, of an initial asparaginase activity of the polyalkylene oxide-asparaginase is retained during the storage period). 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.” See also MPEP 2112.01(II) which states, “…if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” Moreover, Angiolillo and Zalipsky provide evidence that support the inherency of improved retention of the asparaginase activity during storage at 2-8ºC for at least 30 months. 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). Since the liquid composition rendered obvious by the references includes calaspargase pegol, then improved stability of the enzyme activity would have been necessarily possessed by the liquid composition rendered by the references (Soares in view of Oncaspar, Angiolillo, and Zalipsky) based on Angiolillo and Zalipsky, relative to the liquid composition of Soares comprising PEG-L-asparaginase in which the L-asparaginase is pegylated with a succinimidyl succinate linker (SS-PEG).
As such, Soares in view of Oncaspar, Angiolillo, and Zalipsky renders obvious instant claims 153, 161, and 170-172.
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 days falls 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 April 27, 2026, with respect to the rejection under 35 U.S.C. 112(b) of claims 153-157, 159-161, and 170 have been fully considered and are persuasive. The rejection under 35 U.S.C. 112(b) has been overcome by the amendments to claims 153 and 161, deleting the recitation “substantially the same.” Therefore, this rejection has been withdrawn.
The amendments to the claims necessitated modifying the rejection under 35 U.S.C. 112(a) and the rejection under 35 U.S.C. 103 over Soares in view of Oncaspar, Angiolillo, and Zalipsky. Applicant’s arguments are unpersuasive with respect to these rejections.
Regarding the rejection under 35 U.S.C. 112(a), Applicant asserts that the specification expressly states that the compositions of the invention include both liquid compositions and lyophilized, storage-stable compositions, citing page 56 for example, which refers to both stabilized liquid and lyophilized compositions as “compositions of the invention.” The Examiner does not find any explicit recitation anywhere in the specification, including page 56, of “compositions of the invention” or “stabilized” liquid compositions. However, the specification on page 6, lines 29-30 does recite, “Aspects of the invention include lyophilized storage stable polyalkylene oxide-asparaginase compositions.” Applicant then argues that a person of ordinary skill in the art would therefore understand that the term “compositions of the invention” encompasses at least the example compositions, including the composition expressly disclosed in Example 2, which is a liquid composition (Table 25) and is not limited solely to lyophilized compositions. The Examiner agrees that the specification discloses both liquid compositions (such as the liquid composition of Example 2) and lyophilized storage stable polyalkylene oxide-asparaginase compositions.
Then, Applicant asserts that is it customary for applicants to provide examples of their best embodiments, which are understood to be preferred because they have been tested. Accordingly, Applicant argues that a person of ordinary skill in the art would recognize that the disclosure passages relating to stability (e.g., the definition of “stabilized” on pages 14-15, including the disclosures that a storage stable composition retains “90% or more” of its activity, that an extended period of time includes “2.5 years (e.g., 30 months) or more,” and that a storage stable composition is substantially stable at “2 to 8ºC”) are not confined to lyophilized compositions, but also extend to stabilized liquid compositions of the invention, such as the SC-linker-containing compositions described in Example 2. However, the discussion regarding stability on pages 14-15 (the paragraph that begins on page 14, line 13 and ends on page 15, lines 25) of the specification is only with respect to a lyophilized composition, particularly because of the beginning of the paragraph, specifically page 14, lines 13-19. While page 56, line 30 through page 57, line 24, refers to a “storage stable composition,” there is no clear statement that this paragraph of the specification is in reference to any of the liquid compositions disclosed in the specification, including the liquid composition of Example 2. Therefore, Applicant’s arguments are unpersuasive with respect to the rejection under 35 U.S.C. 112(a).
Regarding the rejection under 35 U.S.C. 103, Applicant asserts that Soares is the only reference that actually tests liquid stability, demonstrating only that PEG-asparaginase was stable at 8ºC for “a longer period than one month” (page 168, left column, second-to-last paragraph). Applicant argues that the gap between “a longer period than one month” and the claimed “at least 30 months” with 90% or more activity retention, is enormous and unpredictable. Applicant then asserts that Soares provides no teaching or suggestion that a liquid PEG-asparaginase composition would retain 90% or more of its activity for 30 months. However, the Examiner disagrees that there is a gap between “a longer period than one month” and “at least 30 months” – the difference between the two ranges is the lower limit, and “a longer period than one month” encompasses periods that fall within the claimed “at least 30 months,” such as 35 months. The teaching of “a longer period than one month” in Soares encompasses time periods falling in the claimed range of “at least 30 months.”
Furthermore, Applicant points out that Angiolillo’s teaching that the SC linker is “more stable” and imparts “improved drug product shelf life” is qualitative, not quantitative, citing page 3874, second paragraph; and page 3880, first paragraph. Applicant argues that Angiolillo studies in vivo pharmacokinetics, not shelf-life stability of liquid formulations. Applicant further asserts that the teaching that a linker is “more stable” does not predict that a liquid composition would retain 90% or more of its activity for 30 or more months. However, the teaching of “improved drug product shelf life” in Angiolillo supports the finding of the claimed stability property being necessarily possessed by the liquid composition rendered obvious by the references in the rejection under 35 U.S.C. 103. The rejection recognizes that the art does not expressly disclose the claimed stability property (recited in terms of asparaginase activity retention), and cites MPEP 2112(I) which states that, “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.’” Also, MPEP 2112(II) sets forth that an inherent feature need not be recognized at the relevant time. Though the claimed stability property is not appreciated by the cited references, it does not mean that the composition rendered obvious by the references does not possess the claimed stability property. Applicant also asserts that many factors beyond the linker affect liquid formulation stability, including protein concentration, buffer species, pH, ionic strength, and container interactions. However, Applicant has not provided evidence to support this assertion. Also, the references render obvious a composition comprising the same protein (the polyalkylene-oxide asparaginase), the same buffer (the sodium phosphates), and the same salt (sodium chloride) at the same concentrations as claimed, so the liquid formulation stability necessarily would have been the same as claimed. As indicated in MPEP 2112.01(I), “Where 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.” Also, MPEP 2112.01(II) sets forth that, “…if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Additionally, Applicant asserts that the inherency argument set forth in the rejection is improper. Applicant argues that the Office Action has not established that any liquid composition of SC-PEG-asparaginase in phosphate buffer would necessarily retain 90% or more activity for 30 months or more at 2-8ºC. However, the rejection does not set forth that just any composition of SC-PEG-asparaginase in phosphate buffer would necessarily have the claimed activity retention. Instead, the basis of the rejection is that since the references render 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 have the claimed stability property.
Applicant asserts that protein stability in liquid formulations is notoriously unpredictable. It is then asserted that the fact that the SC linker is “more stable” than the SS linker does not mean that a liquid formulation containing SC-PEG-asparaginase would necessarily achieve the specific degree of long-term stability now claimed. However, the SC linker being more stable is rationale provided in the rejection to support the determination that the claimed stability property necessarily flows from the teachings of the cited references. Further still, Applicant asserts that the stability of a liquid pharmaceutical formulation depends on many factors beyond linker hydrolysis – including protein aggregation, deamidation, oxidation and other degradation pathways. Applicant asserts that the prior art does not establish that improved linker stability alone would result in specific degree of long-term liquid formulation stability now claimed (90% or more activity retention for at least 30 months). However, the rationale of the rejection is that since the references render obvious a liquid composition consisting of the same components at the same concentrations as claimed, then the liquid composition rendered obvious by the references necessarily possesses the claimed stability property (claimed asparaginase activity retention). The evidence of linker stability of Angiolillo and Zalipsky supports this rationale. Regarding the other factors beyond linker hydrolysis argued by Applicant, the levels of protein aggregation, deamidation, oxidation, and other degradation pathways would have been expected to be the same for the liquid composition rendered obvious by the references as the claimed liquid composition because the references render obvious a liquid composition consisting of the claimed components in the claimed concentrations. In traversing the rejection, Applicant has not persuasively proven that the prior art composition does not necessarily possess the stability in terms of asparaginase activity retention of the claimed composition.
Additionally, Applicant submits that the Examiner’s position – that the claimed stability of the asparaginase formulation is merely an inherent property of the prior art combination – is legally insufficient to sustain the obviousness rejection. In particular, Applicant argues that unexpected properties may render an otherwise obvious combination nonobvious, and cites Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A. DE C.V., 865 F.3d 1348 (Fed. Cir. 2017). Other than the claimed stability property, the differences between Soares and the claimed liquid composition is the concentration of the polyalkylene oxide-asparaginase and the linker. Angiolillo and Zalipsky support the expectation of improved asparaginase activity retention during storage when Soares is modified by substituting the PEG-L-asparaginase with calaspargase pegol (possessing the claimed linker and having improved drug product shelf life). Applicant has not provided evidence that the claimed polyalkylene oxide-asparaginase concentration is critical for improving the stability property (the asparaginase activity retention during storage). Applicant asserts that the experimental data of record show that the claimed formulation maintains enzyme activity and resists degradation under conditions in which prior art asparaginase formulations exhibit significantly reduced stability. However, the Examiner respectfully submits that Applicant has not provided such evidence.
In particular, Applicant cites the Wright Declaration previously filed on June 30, 2025, for demonstrating that Asparlas (which corresponds to the claimed composition, specifically the formulation in Table 25 of the specification, with the exception that Table 25 recites 1.29 mg of monobasic sodium phosphate instead of 1.20 mg as in Asparlas; see footnote 1 of the Declaration) achieves a 36-month shelf life compared to only 8 months for liquid Oncaspar – a 4.5-fold improvement. Both Asparlas and Oncaspar comprise their polyalkylene oxide-asparaginase, buffers (dibasic sodium phosphate, monobasic sodium phosphate), and salt (sodium chloride) in water at the same concentrations, the only difference being that Asparlas includes calaspargase pegol instead of pegaspargase of Oncaspar as the polyalkylene oxide-asparaginase. See page 4, Section 11 of the Oncaspar reference cited as a reference in the rejection under 35 U.S.C. 103, compared with footnote 1 of the Declaration. The Declaration sets forth that due to the SC linker, Asparlas has a significantly longer shelf life (36 months) compared to liquid Oncaspar (8 months) (paragraph 5 of the Declaration). However, the Declaration does not set forth the stability in terms of the retention of asparaginase activity during a storage period of at least 30 months at 2-8ºC. The Declaration does not set forth that the longer shelf life is the shelf life when the liquid composition is stored at 2-8ºC, such that 90% or more of an initial asparaginase activity of the polyalkylene oxide-asparaginase is retained during the storage period. Moreover, the improved shelf life determined in the Declaration is not an unexpected result 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). The teachings of Angiolillo and Zalipsky support a finding that the improved shelf life of the Declaration is expected.
Finally, Applicant submits that there is a critical distinction between linker stability (what Angiolillo teaches) and overall liquid formulation stability (what is claimed). It is argued that the stability of a liquid pharmaceutical formulation depends on many factors beyond linker hydrolysis. However, the Declaration compares two formulations in which the only difference is the linker of the asparaginase. Moreover, as pointed out above, the Declaration does not set forth the shelf life in terms of asparaginase activity retention of 90% or more at 2-8ºC. Therefore, Applicant has not persuasively demonstrated an unexpected result to overcome the rejection under 35 U.S.C. 103.
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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/SUSAN E. FERNANDEZ/ Examiner, Art Unit 1651
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