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 .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed April 9, 2026. The amendment, filed April 9, 2026, is entered, wherein claims 32 – 33, 35, 46 – 47, 49, 60 – 61, and 63 are amended, claims 43 – 45, 57 – 59, and 71 – 73 are withdrawn, and claims 1 – 31, 36, 50, and 64 are canceled.
Claims 32 – 35, 37 – 49, 51 – 63, and 65 – 71 are pending in this application and claims 32 – 35, 37 – 42, 46 – 49, 51 – 56, 60 – 63, and 65 – 70 are currently examined.
Priority
3. This application is a national stage application of PCT/IL2021/050137, filed February 4, 2021, which claims benefit of domestic application 62/969,769, filed February 4, 2020.
Withdrawn Rejections
4. The rejection of claims 32 – 35, 40 – 42, 46 – 49, 54 – 56, 60 – 63, and 68 – 70 in the previous Office Action, mailed January 9, 2026, under 35 U.S.C. 102(a)(1) as being anticipated by Gengrinovitch has been considered and is withdrawn in view of the amended claim 32.
The rejection of claims 32 – 36, 38 – 42, 46 – 50, 52 – 56, 60 – 64, and 66 – 70 in the previous Office Action, mailed January 9, 2026, under 35 U.S.C. 103 as being unpatentable over Gengrinovitch (WO2017/093993A1) in view of Zhang has been considered and is withdrawn in view of the amended claim 32.
The rejection of claims 37, 51, and 65 in the previous Office Action, mailed January 9, 2026, under 35 U.S.C. 103 as being unpatentable over Gengrinovitch in view of Zhang as applied to claims 32 – 36, 38 – 42, 46 – 50, 52 – 56, 60 – 64, and 66 – 70 above, and further in view of Carneiro et al. has been considered and is withdrawn in view of the amended claim 32.
The rejection of claims 32 and 46 in the previous Office Action, mailed January 9, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2 and 9 of U.S. Patent No. 8993278B2 has been considered and is withdrawn in view of the amended claim 32.
The rejection of claims 32 – 35, 40 – 42, 46 – 49, 54 – 56, 60 – 63, and 68 – 70 in the previous Office Action, mailed January 9, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10, and 13 of U.S. Patent No. 11058701B2 in view of Gengrinovitch has been considered and is withdrawn in view of the amended claim 32.
The rejection of claims 32 – 35, 40 – 42, 46 – 49, 54 – 56, 60 – 63, and 68 – 70 in the previous Office Action, mailed January 9, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 8 of U.S. Patent No. 11104698B2 in view of Gengrinovitch has been considered and is withdrawn in view of the amended claim 32.
The rejection of claims 32 – 35, 40 – 42, 46 – 49, 54 – 56, 60 – 63, and 68 – 70 in the previous Office Action, mailed January 9, 2026, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6 – 7, and 10 of U.S. Patent No. 12064445B2 in view of Gengrinovitch has been considered and is withdrawn in view of the amended claim 32.
The following are new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed April 9, 2026, wherein claims 32 – 33, 35, 46 – 47, 49, 60 – 61, and 63 are amended, claims 43 – 45, 57 – 59, and 71 – 73 are withdrawn, and claims 1 – 31, 36, 50, and 64 are canceled. Previously and newly cited references have been used to establish the new grounds of rejection.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 35, 49, and 63 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 35, 49, and 63 ultimately depend from claims 32, 46, and 60, respectively. Claims 32, 46, and 60 require that the water soluble stabilizer and/or solubilizer comprises poloxamer or a combination of poloxamer and PVP. Claims 35, 49, and 63 recite that the water soluble linear polymer comprises poloxamer, PVP, or a combination thereof. Therefore, claims 35, 49, and 63 is satisfied by the same poloxamer and/or PVP already required by the claims from which they ultimately depend and do not necessarily specify a further limitation of the claimed subject matter. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
New Claim Rejections - 35 USC § 103
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.
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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 32 and 40 – 41 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Machine Translation of CN107137417A, hereinafter Zhang ‘417, cited in the PTO-892 on January 9, 2026).
a. Zhang ‘417 teaches the use of cytarabine or analogues thereof and ketorolac or analogues thereof in the treatment of cachexia, and a pharmaceutical composition for treating cachexia. The cytarabine analogs include prodrugs of cytarabine, wherein the cytarabine prodrug is Astarabine (Abstract). In one embodiment, the pharmaceutical composition is an injection solution and the specific prescription of the injection solution is: 20 parts by weight of cytarabine, 10 parts by weight of ketorolac tromethamine, and increased 2 parts by weight of the solubilizer poloxamer, 15 parts by weight of the isotonicity adjusting agent sodium chloride, an appropriate amount of the pH adjuster (pH adjusted to 7.0 – 7.4), and 50 parts by weight of water for injection (page 5 – 6, Example 5).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate Astarabine, a prodrug of cytarabine, in the pharmaceutical composition, such as an injection formulation comprising poloxamer, as taught by Zhang ‘417 because Zhang ‘417 teaches the use of cytarabine or cytarabine analogs/prodrugs for the same therapeutic purpose and provides a pharmaceutical injection composition containing cytarabine and poloxamer. Zhang ‘417 teaches cytarabine and cytarabine analogs/prodrugs, such as Astarabine, for treating cachexia, and further teaches a pharmaceutical injection composition comprising cytarabine and poloxamer. Thus, the claimed composition results from selecting a known cytarabine-based alternative active agent from the alternatives taught by Zhang ‘417 and using it in the disclosed poloxamer formulation of Zhang ‘417. One of ordinary skill in the art would have had a reasonable expectation of success to incorporate Astarabine, a prodrug of cytarabine, in the pharmaceutical composition, such as an injection formulation comprising poloxamer, as taught by Zhang ‘417 because substituting the cytarabine prodrug for cytarabine would have involved the simple substitution of one known cytarabine-based active agent for another known cytarabine-based active agent to obtain the predictable result.
Claims 33 – 35, 38 – 39, 42, 60 – 63, and 66 – 70 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Machine Translation of CN107137417A, hereinafter Zhang ‘417, cited in the PTO-892 on January 9, 2026) as applied to claims 32 and 40 – 41 above, and further in view of Gengrinovitch (WO2017/093993A1, cited in the PTO-892 on January 9, 2026).
b. Zhang ‘417 teaches the limitations discussed above.
However, Zhang ‘417 does not teach the at least one water soluble stabilizer and/or solubilizer further comprises a linear polymer, wherein the linear polymer is non-ionic, wherein the water soluble linear polymer further comprises linear polymer recited in claims 35 and 63. Zhang ‘417 does not teach the aspacytarabine is a salt of hydrochloride. Zhang ‘417 does not teach the concentration of aspacytarabine within the composition in aqueous solution is between 20 – 1000 mg/mL.
Gengrinovitch teaches prodrugs comprising cytarabine conjugated to a single amino acid, asparagine, for use in treating neoplastic diseases in medically compromised subjects (page 5, lines 3 – 6). According to one embodiment, the compound is Astarabine® and the pharmaceutically acceptable salt is hydrochloride salt (page 6, lines 3 – 4; page 7, lines 6 – 7). Gengrinovitch teaches that the prodrug may be presented in the form of pharmaceutical compositions comprising Astarabine® and a pharmaceutically acceptable carrier or diluent, optionally further comprising one or more excipients, wherein the carrier may be polyethylene glycol. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered (page 17, lines 24 – 33). According to some embodiments, the route of administration is via parenteral administration (page 23, lines 29 – 30). In one example, the drug Astarabine® is supplied as a sterile lyophilized powder in glass ampoules of 1 g per ampoule. The drug is dissolved in 10 mL of sterile water for injection to obtain a final concentration of Astarabine® of 100 mg/mL (page 29, lines 24 – 26).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection as taught by Zhang ‘417 with PEG as a pharmaceutically acceptable carrier in view of Gengrinovitch because Zhang ‘417 teaches an injectable cytarabine-based formulation that already includes multiple pharmaceutically acceptable excipients, including poloxamer as a solubilizer, sodium chloride, a pH adjuster, and water for injection and it is known in the art to formulate aspacytarabine with PEG. Gengrinovitch teaches pharmaceutical compositions comprising Astarabine® and a pharmaceutically acceptable carrier or diluent, optionally further comprising one or more excipients, wherein the carrier may be PEG. It would have been obvious to combine the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection as taught by Zhang ‘417 with PEG as a pharmaceutically acceptable carrier in view of Gengrinovitch because the combination would yield predictable results. One of ordinary skill in the art would have had a reasonable expectation of success to combine the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection as taught by Zhang ‘417 with PEG as a pharmaceutically acceptable carrier in view of Gengrinovitch because Zhang ‘417 teaches that a cytarabine-based injectable formulation may be prepared with conventional formulations excipients and Gengrinovitch teaches PEG as a pharmaceutically acceptable carrier for the same cytarabine prodrug. Therefore, the combination of Zhang ‘417 and Gengrinovitch reads on the limitations of claims 33 – 35, and 61 – 63.
Regarding claims 38- 39 and 66 – 67, Zhang ‘417 and Gengrinovitch teach the compositions of claims 33 and 61 as discussed above. Gengrinovitch teaches that pharmaceutical compositions of aspacytarabine may further comprise pharmaceutically acceptable excipients, carriers, stabilizers, and agents that increase solubility, including PEG. Zhang ‘417 teaches an aqueous injectable cytarabine-based formulation comprising 20 parts by weight active agent and 2 parts by weight poloxamer, corresponding to an active agent:solubilizing polymer weight ratio of 10:1 and about 2.1 wt% poloxamer in the formulation. Thus, Zhang ‘417 teaches the use of a water-soluble polymeric solubilizer in an aqueous cytarabine-based formulation at an amount falling within the claimed ranges. It would have been obvious to one of ordinary skill in the art to optimize the amount of additional water-soluble linear polymer, such as PEG taught by Gengrinovitch, in the aspacytarabine/poloxamer formulation. The amount of a solubilizing/stabilizing polymer is a result-effective variable because Gengrinovitch teaches the use of stabilizers and agents that increase solubility to allow preparation of concentrated solutions and Zhang ‘417 identifies poloxamer as a solubilizer in an aqueous cytarabine-based formulation. Therefore, one of ordinary skill in the art would have been motivated to use an amount of PEG sufficient to improve or maintain solubility and stability, including amounts within the broad claimed ranges of 99:1 to 1:10 active agent:linear polymer and 0.1% to 30% w/w linear polymer. Applicant has not shown that the claimed ranges are critical or produce unexpected results. Although the poloxamer disclosed by Zhang ‘417 is not relied upon as the additional linear polymer of claims 33 and 61, Zhang ‘417 demonstrates that polymeric solubilizers are conventionally used in such formulations at amounts within the claimed ranges. Therefore, it would have been obvious to select and optimize the amount of the additional PEG taught by Gengrinovitch, including amounts within the broad claimed ranges.
Regarding claims 42, 60, and 70, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of Zhang ‘417, as discussed above, to use the hydrochloride salt of aspacytarabine at a concentration of 100 mg/mL as taught by Gengrinovitch because Gengrinovitch is directed to the same cytarabine prodrug, aspacytarabine, and teaches an intravenous aqueous formulation of the hydrochloride salt. Thus, Gengrinovitch teaches a known pharmaceutically acceptable salt form and a known injectable concentration for the same active agent. One would have been motivated to use the hydrochloride salt and 100 mg/mL concentration taught by Gengrinovitch in the aqueous injectable pharmaceutical composition of Zhang ‘417 because Gengrinovitch teaches those features as suitable for intravenous administration of the same active agent. One of ordinary skill in the art would have had a reasonable expectation of success to modify the composition of Zhang ‘417, as discussed above, to use the hydrochloride salt of aspacytarabine at a concentration of 100 mg/mL as taught by Gengrinovitch because Gengrinovitch teaches the same cytarabine prodrug formulated for intravenous administration as an aqueous solution.
Regarding claims 68 – 69, Zhang ‘417 teaches the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster (pH adjusted to 7.0 – 7.4), and water for injection. The limitations of claims 68 – 69 are met.
Claims 37 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Machine Translation of CN107137417A, hereinafter Zhang ‘417, cited in the PTO-892 on January 9, 2026) and Gengrinovitch (WO2017/093993A1, cited in the PTO-892 on January 9, 2026) as applied to claims 32 – 35, 40 – 42, 60 – 63, and 68 – 70 above, and further in view of Carneiro et al. (International Journal of Molecular Sciences, 2019, Vol. 20, Issue 3, cited in the PTO-892 on January 9, 2026).
c. Zhang ‘417 and Gengrinovitch teach the limitations discussed above. Gengrinovitch further teaches that the pharmaceutical composition comprising aspacytarabine or a pharmaceutically acceptable salt thereof may be in a form of aqueous injection suspension. The suspension may also contain suitable stabilizers or agent which increase the solubility of the compound to allow for the preparation of highly concentrated solutions (page 20, lines 5 – 6).
However, Zhang ‘417 and Gengrinovitch do not teach the composition comprising cyclodextrin.
Carneiro et al. disclose cyclodextrin-drug inclusion complexes (Title), whereas cyclodextrins play a vital role in the development of inclusion complexes which promote improvements in the chemical and biological properties of the complexed active principles, as well as providing improved solubility and aqueous stability (Abstract). Moreover, cyclodextrins are considered safe for parenteral administration and are commonly used with antitumor and immunomodulatory drugs. The FDA approves pharmaceutical formulations containing liposomal preparations of cytarabine, which have proven to be attractive and less toxic alternatives to the conventional drug formulations. Therefore, cyclodextrins are well tolerated, atoxic if used in safe concentration ranges and are considered safe for complexion with drugs (page 3, para. 2). Inclusion complexes formed with a host-guest molecule may exhibit improved chemical or biological properties compared to the host molecule alone. Such inclusion may improve aqueous solubility, dissolution, and bioavailability; increase the physiochemical stability of drugs and improve the shelf life of drugs; modify the drug delivery site and/or the time profile; reduce or eliminate unpleasant taste and smell; prevent drug-drug or drug-excipient interactions; and convert liquid drugs into microcrystalline or amorphous powders (page 3, para. 3).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Zhang ‘417 and Gengrinovitch, which comprising aspacytarabine, PEG, and poloxamer, to further include cyclodextrin in view of Carneiro et al. because Zhang ‘417 teaches an injectable pharmaceutical composition for a cytarabine-based active agent and explicitly identifies poloxamer as a solubilizer, thereby recognizing the need to solubilize the cytarabine-based active agent in the pharmaceutical formulation, Gengrinovitch teaches that the solubility of aspacytarabine might need to be increase for the preparation of higher concentrated solutions, and Carneiro et al. teach that cyclodextrin form drug inclusion complexes and are useful pharmaceutical excipients for improving the solubility, aqueous stability, dissolution, bioavailability, physiochemical stability, and shelf-life of drugs. Carneiro et al. further teach that cyclodextrins are suitable for pharmaceutical use, including parenteral administration. Thus, one would have been motivated to include cyclodextrin in the injectable cytarabine prodrug composition of Zhang ‘417 and Gengrinovitch to improve the formulation properties of the active agent, particularly solubility and stability in an aqueous pharmaceutical composition. One of ordinary skill in the art would have had a reasonable expectation of success to modify the pharmaceutical composition of Zhang ‘417 and Gengrinovitch, which comprising aspacytarabine, PEG, and poloxamer, to further include cyclodextrin in view of Carneiro et al. because Zhang ‘417 already teaches use of a solubilizer in the cytarabine-based injectable formulation, Gengrinovitch teaches the need of stabilizer or agents to increase the solubility of aspacytarabine for preparing a higher concentrated solutions, and Carneiro et al. teach cyclodextrin inclusion complexation as a known pharmaceutical technique for improving solubility and stability.
Claims 46 and 54 – 55 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Machine Translation of CN107137417A, hereinafter Zhang ‘417, cited in the PTO-892 on January 9, 2026) in view of Zhang et al. (US7550155B2, hereinafter ‘155B2, Reference included with PTO-892).
d. Zhang ‘417 teaches the use of cytarabine or analogues thereof and ketorolac or analogues thereof in the treatment of cachexia, and a pharmaceutical composition for treating cachexia. The cytarabine analogs include prodrugs of cytarabine, wherein the cytarabine prodrug is Astarabine (Abstract). In one embodiment, the pharmaceutical composition is an injection solution and the specific prescription of the injection solution is: 20 parts by weight of cytarabine, 10 parts by weight of ketorolac tromethamine, and increased 2 parts by weight of the solubilizer poloxamer, 15 parts by weight of the isotonicity adjusting agent sodium chloride, an appropriate amount of the pH adjuster (pH adjusted to 7.0 – 7.4), and 50 parts by weight of water for injection (page 5 – 6, Example 5).
However, Zhang ‘417 does not teach that the compositions is chemically and physically stable when stored at a temperature between -80 to 30 ⁰C for at least 1 month and for at least 24 hrs when formulated as an aqueous solution.
‘155B2 teaches aqueous pharmaceutical formulations comprising a drug, water, polyethylene glycol, and a block copolymer surfactant such as poloxamer (Abstract). ‘155B2 further teaches that poloxamers 188 is one poloxamer that is approved for use in pharmaceutical preparation for administration to humans and, in particular approved for use in intravenous and/or other injectable formulations (Col. 12, lines 66 – 67; Col. 13, lines 1 – 3).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate Astarabine, a prodrug of cytarabine, in the pharmaceutical composition, such as an injection formulation comprising poloxamer, as taught by Zhang ‘417 because Zhang ‘417 teaches the use of cytarabine or cytarabine analogs/prodrugs for the same therapeutic purpose and provides a pharmaceutical injection composition containing cytarabine and poloxamer. Zhang ‘417 teaches cytarabine and cytarabine analogs/prodrugs, such as Astarabine, for treating cachexia, and further teaches a pharmaceutical injection composition comprising cytarabine and poloxamer. Thus, the claimed composition results from selecting a known cytarabine-based alternative active agent from the alternatives taught by Zhang ‘417 and using it in the disclosed poloxamer formulation of Zhang ‘417. One of ordinary skill in the art would have had a reasonable expectation of success to incorporate Astarabine, a prodrug of cytarabine, in the pharmaceutical composition, such as an injection formulation comprising poloxamer, as taught by Zhang ‘417 because substituting the cytarabine prodrug for cytarabine would have involved the simple substitution of one known cytarabine-based active agent for another known cytarabine-based active agent to obtain the predictable result.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to select poloxamer 188 in view of ‘155B2 as the poloxamer in the injectable pharmaceutical composition of Zhang ‘417 because Zhang ‘417 teaches an injectable cytarabine-based pharmaceutical composition comprising poloxamer as a solubilizer, sodium chloride, a pH adjuster, and water for injection. Although Zhang ‘417 does not explicitly identify the particular poloxamer species, the disclosure of “poloxamer” in Zhang ‘417 broadly encompasses known poloxamer species. ‘155B2 teaches that poloxamers useful in pharmaceutical formulations include poloxamer 188 and further teaches that poloxamer 188 is approved for pharmaceutical preparations, including intravenous and/or other injectable formulations. Thus, one of ordinary skill in the art would have been motivated to select poloxamer 188 as the poloxamer used in the injectable pharmaceutical composition of Zhang ‘417. One of ordinary skill in the art would have had a reasonable expectation of success to select poloxamer 188 in view of ‘155B2 as the poloxamer in the injectable pharmaceutical composition of Zhang ‘417 because the selection involves choosing a known pharmaceutical acceptable injectable poloxamer species from the poloxamer genus already taught by Zhang ‘417 for use in an aqueous injectable formulation and ‘155B2 teaches that poloxamer 188 is the known approved poloxamer for use in pharmaceutical preparations for administration to humans and in particular approved for use in intravenous and/or other injectable formulations.
Regarding the claimed stability, Zhang ‘417 teaches the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection. Zhang ‘417 further teaches pH adjustment to about 7.0 – 7.4 for the injection solution. Example 5 of Zhang ‘417 contains 20 parts by weight of cytarabine and 2 parts by weight of poloxamer, corresponding to a 10:1 active agent:poloxamer weight ratio. Zhang ‘417 further teaches cytarabine analogs/prodrugs, including aspacytarabine, for the same therapeutic purpose. Zhang ‘417 does not explicitly identify the particular poloxamer as poloxamer 188 or explicitly recite the claimed chemical and physical stability. However, ‘155B2 teaches aqueous pharmaceutical formulations comprising a drug, water, PEG, and a block copolymer surfactant such as poloxamer and ‘155B2 further teaches that poloxamer 188 is particularly approved for pharmaceutical preparations, including intravenous and/or other injectable formulations. Thus, it would have been obvious to select poloxamer 188 as the particular poloxamer in the injectable cytarabine-based formulation of Zhang ‘417 because Zhang ‘417 teaches poloxamer as a solubilizer in an aqueous injectable formulation and ‘155B2 teaches poloxamer 188 as a known and approved poloxamer for injectable pharmaceutical formulations. The resulting obvious composition would comprise aspacytarabine, poloxamer 188, and an active agent:poloxamer ratio of 10:1. The present specification shows that aspacytarabine/poloxamer 188 compositions at a 10:1 weight ratio are stable for at least 3 months at 2 – 8 ⁰C and 25 ⁰C (Figure 2B; para. [0012]; para. [0090]). The specification further states that composition comprising aspacytarabine or a pharmaceutical acceptable salt thereof and poloxamer provides stable solution with solubility above 50 mg/mL (para. [0089] and that the stability is due to the use of at least one water soluble linear polymer (para. [0092]). Because the obvious composition includes the same active agent, the same poloxamer 188, and the same 10:1 active agent:poloxamer ratio identified in the specification as providing stability, the claimed chemical and physical stability, including stability for at least one month under the claimed storage conditions and for at least 24 hours when formulated as an aqueous solution, would have been an inherent property of the resulting obvious composition.
Claims 47 – 49, 52 – 53, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Machine Translation of CN107137417A, hereinafter Zhang ‘417, cited in the PTO-892 on January 9, 2026) in view of Zhang et al. (US7550155B2, hereinafter ‘155B2, Reference included with PTO-892) as applied to claims 46 and 54 – 55 above, and further in view of Gengrinovitch (WO2017/093993A1, cited in the PTO-892 on January 9, 2026).
e. Zhang ‘417 and ‘155B2 teach the limitations discussed above.
However, Zhang ‘417 and ‘155B2 do not teach the at least one water soluble stabilizer and/or solubilizer further comprises a linear polymer, wherein the linear polymer is non-ionic, wherein the water soluble linear polymer further comprises PEG. Zhang ‘417 and ‘155B2 do not teach the aspacytarabine is a salt of hydrochloride..
Gengrinovitch teaches prodrugs comprising cytarabine conjugated to a single amino acid, asparagine, for use in treating neoplastic diseases in medically compromised subjects (page 5, lines 3 – 6). According to one embodiment, the compound is Astarabine® and the pharmaceutically acceptable salt is hydrochloride salt (page 6, lines 3 – 4; page 7, lines 6 – 7). Gengrinovitch teaches that the prodrug may be presented in the form of pharmaceutical compositions comprising Astarabine® and a pharmaceutically acceptable carrier or diluent, optionally further comprising one or more excipients, wherein the carrier may be polyethylene glycol. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered (page 17, lines 24 – 33). According to some embodiments, the route of administration is via parenteral administration (page 23, lines 29 – 30). In one example, the drug Astarabine® is supplied as a sterile lyophilized powder in glass ampoules of 1 g per ampoule. The drug is dissolved in 10 mL of sterile water for injection to obtain a final concentration of Astarabine® of 100 mg/mL (page 29, lines 24 – 26).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection as taught by Zhang ‘417 with PEG as a pharmaceutically acceptable carrier in view of Gengrinovitch because Zhang ‘417 teaches an injectable cytarabine-based formulation that already includes multiple pharmaceutically acceptable excipients, including poloxamer as a solubilizer, sodium chloride, a pH adjuster, and water for injection and it is known in the art to formulate aspacytarabine with PEG. Gengrinovitch teaches pharmaceutical compositions comprising Astarabine® and a pharmaceutically acceptable carrier or diluent, optionally further comprising one or more excipients, wherein the carrier may be PEG. It would have been obvious to combine the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection as taught by Zhang ‘417 with PEG as a pharmaceutically acceptable carrier in view of Gengrinovitch because the combination would yield predictable results. One of ordinary skill in the art would have had a reasonable expectation of success to combine the injection composition comprising a cytarabine-based active agent, poloxamer, sodium chloride, pH adjuster, and water for injection as taught by Zhang ‘417 with PEG as a pharmaceutically acceptable carrier in view of Gengrinovitch because Zhang ‘417 teaches that a cytarabine-based injectable formulation may be prepared with conventional formulations excipients and Gengrinovitch teaches PEG as a pharmaceutically acceptable carrier for the same cytarabine prodrug. Therefore, the combination of Zhang ‘417 and Gengrinovitch reads on the limitations of claims 47 – 49.
Regarding claims 52 – 53, Zhang ‘417 and Gengrinovitch teach the compositions of claim 47 as discussed above. Gengrinovitch teaches that pharmaceutical compositions of aspacytarabine may further comprise pharmaceutically acceptable excipients, carriers, stabilizers, and agents that increase solubility, including PEG. Zhang ‘417 teaches an aqueous injectable cytarabine-based formulation comprising 20 parts by weight active agent and 2 parts by weight poloxamer, corresponding to an active agent:solubilizing polymer weight ratio of 10:1 and about 2.1 wt% poloxamer in the formulation. Thus, Zhang ‘417 teaches the use of a water-soluble polymeric solubilizer in an aqueous cytarabine-based formulation at an amount falling within the claimed ranges. It would have been obvious to one of ordinary skill in the art to optimize the amount of additional water-soluble linear polymer, such as PEG taught by Gengrinovitch, in the aspacytarabine/poloxamer formulation. The amount of a solubilizing/stabilizing polymer is a result-effective variable because Gengrinovitch teaches the use of stabilizers and agents that increase solubility to allow preparation of concentrated solutions and Zhang ‘417 identifies poloxamer as a solubilizer in an aqueous cytarabine-based formulation. Therefore, one of ordinary skill in the art would have been motivated to use an amount of PEG sufficient to improve or maintain solubility and stability, including amounts within the broad claimed ranges of 99:1 to 1:10 active agent:linear polymer and 0.1% to 30% w/w linear polymer. Applicant has not shown that the claimed ranges are critical or produce unexpected results. Although the poloxamer disclosed by Zhang ‘417 is not relied upon as the additional linear polymer of claim 47, Zhang ‘417 demonstrates that polymeric solubilizers are conventionally used in such formulations at amounts within the claimed ranges. Therefore, it would have been obvious to select and optimize the amount of the additional PEG taught by Gengrinovitch, including amounts within the broad claimed ranges.
Regarding claim 56, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of Zhang ‘417, as discussed above, to use the hydrochloride salt of aspacytarabine at a concentration of 100 mg/mL as taught by Gengrinovitch because Gengrinovitch is directed to the same cytarabine prodrug, aspacytarabine, and teaches an intravenous aqueous formulation of the hydrochloride salt. Thus, Gengrinovitch teaches a known pharmaceutically acceptable salt form and a known injectable concentration for the same active agent. One would have been motivated to use the hydrochloride salt and 100 mg/mL concentration taught by Gengrinovitch in the aqueous injectable pharmaceutical composition of Zhang ‘417 because Gengrinovitch teaches those features as suitable for intravenous administration of the same active agent. One of ordinary skill in the art would have had a reasonable expectation of success to modify the composition of Zhang ‘417, as discussed above, to use the hydrochloride salt of aspacytarabine at a concentration of 100 mg/mL as taught by Gengrinovitch because Gengrinovitch teaches the same cytarabine prodrug formulated for intravenous administration as an aqueous solution.
Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Machine Translation of CN107137417A, hereinafter Zhang ‘417, cited in the PTO-892 on January 9, 2026) in view of Zhang et al. (US7550155B2, hereinafter ‘155B2, Reference included with PTO-892) as applied to claims 46 and 54 – 55 above, and further in view of Gengrinovitch (WO2017/093993A1, cited in the PTO-892 on January 9, 2026) and Carneiro et al. (International Journal of Molecular Sciences, 2019, Vol. 20, Issue 3, cited in the PTO-892 on January 9, 2026).
f. Zhang ‘417 and ‘155B2 teach the limitations discussed above.
However, Zhang ‘417 and ‘155B2 do not teach the composition comprising cyclodextrin.
Gengrinovitch teaches that the pharmaceutical composition comprising aspacytarabine or a pharmaceutically acceptable salt thereof may be in a form of aqueous injection suspension. The suspension may also contain suitable stabilizers or agent which increase the solubility of the compound to allow for the preparation of highly concentrated solutions (page 20, lines 5 – 6).
Carneiro et al. disclose cyclodextrin-drug inclusion complexes (Title), whereas cyclodextrins play a vital role in the development of inclusion complexes which promote improvements in the chemical and biological properties of the complexed active principles, as well as providing improved solubility and aqueous stability (Abstract). Moreover, cyclodextrins are considered safe for parenteral administration and are commonly used with antitumor and immunomodulatory drugs. The FDA approves pharmaceutical formulations containing liposomal preparations of cytarabine, which have proven to be attractive and less toxic alternatives to the conventional drug formulations. Therefore, cyclodextrins are well tolerated, atoxic if used in safe concentration ranges and are considered safe for complexion with drugs (page 3, para. 2). Inclusion complexes formed with a host-guest molecule may exhibit improved chemical or biological properties compared to the host molecule alone. Such inclusion may improve aqueous solubility, dissolution, and bioavailability; increase the physiochemical stability of drugs and improve the shelf life of drugs; modify the drug delivery site and/or the time profile; reduce or eliminate unpleasant taste and smell; prevent drug-drug or drug-excipient interactions; and convert liquid drugs into microcrystalline or amorphous powders (page 3, para. 3).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Zhang ‘417, which comprising aspacytarabine and poloxamer, to further include cyclodextrin in view of Carneiro et al. because Zhang ‘417 teaches an injectable pharmaceutical composition for a cytarabine-based active agent and explicitly identifies poloxamer as a solubilizer, thereby recognizing the need to solubilize the cytarabine-based active agent in the pharmaceutical formulation, Gengrinovitch teaches that the solubility of aspacytarabine might need to be increase for the preparation of higher concentrated solutions, and Carneiro et al. teach that cyclodextrin form drug inclusion complexes and are useful pharmaceutical excipients for improving the solubility, aqueous stability, dissolution, bioavailability, physiochemical stability, and shelf-life of drugs. Carneiro et al. further teach that cyclodextrins are suitable for pharmaceutical use, including parenteral administration. Thus, one would have been motivated to include cyclodextrin in the injectable cytarabine prodrug composition of Zhang ‘417 to improve the formulation properties of the active agent, particularly solubility and stability in an aqueous pharmaceutical composition. One of ordinary skill in the art would have had a reasonable expectation of success to modify the pharmaceutical composition of Zhang ‘417, which comprising aspacytarabine and poloxamer, to further include cyclodextrin in view of Carneiro et al. because Zhang ‘417 already teaches use of a solubilizer in the cytarabine-based injectable formulation, Gengrinovitch teaches the need of stabilizer or agents to increase the solubility of aspacytarabine for preparing a higher concentrated solutions, and Carneiro et al. teach cyclodextrin inclusion complexation as a known pharmaceutical technique for improving solubility and stability.
Response to Applicant’s Remarks:
Applicant’s Remarks, filed April 9, 2026, have been fully considered. Applicant’s arguments are applied to the new rejections set forth above, the arguments are not persuasive for the reason discussed below.
Applicant argues that a stable composition comprising aspacytarabine/BST-236, or a pharmaceutically acceptable salt thereof, would not have been obvious. Applicant asserts that BST-236 HCl is freely soluble in water, but is not stable in aqueous solution because the low pH solution promotes hydrolysis to cytarabine and aspartic acid, resulting in unacceptable cytarabine levels. Applicant further argues that attempts to raise the pH with strong or weak bases caused precipitation of the free base crystalline Form B.
Applicant further argues that merely adding a known solubilizer and/or stabilizer does not solve the precipitation and instability problem. According to Applicant, only a narrow set of formulation parameters, including the selected solubilizer/stabilizer, their concentrations, the duration, and intensity of stirring, and the order of addition, yield the composition that remained physically and chemically stable and suitable for intravenous administration.
Applicant also argues that the claimed formulation is unusually sensitive to mechanical stress. Applicant contends that continuous stirring unexpectedly induced precipitation of Form B, whereas a skilled artisan would have expected agitation to reduce localized supersaturation and discourage crystallization.
For the cyclodextrin claims, Applicant argues that Carneiro et al.’s general disclosure of cyclodextrin inclusion complexes would not have provided a reasonable expectation of success for the specific aspacytarabine formulation because the stability problem depends on a multi-variable interaction that was not predictable from general formulation principles.
These arguments are not persuasive. Applicant has not provided comparative evidence showing that a narrow formulation or narrow set of formulation parameters, including the selected solubilizer/stabilizer, their concentrations, stirring duration, stirring intensity, order of addition, and pH adjustment with NaOH, is required to obtain the presently claimed composition. In particular, Applicant has not provide comparative evidence establishing that the selected solubilizer/stabilizer, their concentrations, stirring duration, stirring intensity, order of addition, or pH adjustment with NaOH are critical to the patentability of the presently rejected composition claims. To the extent Applicant argues that particular concentrations are critical, the rejected claims, under their broadest reasonable interpretation, do not require such particular concentrations or recite broad ranges, and Applicant has not provided comparative evidence showing criticality across the full scope of those claims. The specification has been considered. Although the specification describes certain exemplary formulations and preparation or testing conditions, the specification does not establish that the presently claimed compositions require a narrow critical combination of concentration, stirring, order of addition, or other process parameters. Instead, the specification broadly states that compositions comprising aspacytarabine or a pharmaceutically acceptable salt thereof and poloxamer, PEG, PVP, or combinations thereof provide stable solutions, and further attributes the observed stability and solubility to the use of at least one water soluble linear polymer (para. [0089]; para. [0092]). Thus, Applicant has not shown that the alleged formulation parameters are critical, nor has Applicant shown unexpected results commensurate in scope with the pending composition claims. The current rejection is not based merely on a general assertion that any solubilizer or stabilizer could be substituted into an aspacytarabine formulation. Zhang ‘417 is relied upon for teaching an aqueous parenteral pharmaceutical composition comprising a cytarabine-based active agent and poloxamer. Zhang ‘417 exemplifies using poloxamer as a solubilizer in the injection formulation. Thus, Zhang ‘417 identifies the relevant formulation need, which is solubilizing a cytarabine-based active agent in an aqueous injection pharmaceutical composition, and also provides poloxamer as a known formulation component for that purpose. Zhang ‘417 further teaches cytarabine analogs/prodrugs as suitable active agents. Gengrinovitch is relied upon for teaching the same cytarabine prodrug in hydrochloride salt form for aqueous intravenous formulation at 100 mg/mL. Thus, the applied references are directed to the same type of active agent, the same pharmaceutical route of administration, and known formulation excipients for aqueous injectable compositions.
Applicant’s assertion that aspacytarabine hydrochloride salt may present solubility, pH, precipitation, and stability issues does not overcome the rejection. Those formulation concerns would have provided a reason for one of ordinary skill in the art to use known solubilizing and stabilizing excipients, such as poloxamer as taught by Zhang ‘417, in an aqueous cytarabine/prodrug formulation. Zhang ‘417 does not merely identify the problem; Zhang ‘417 teaches an aqueous cytarabine-based injectable formulation using poloxamer as a solubilizer. Therefore, one of ordinary skill in the art would have had reason to apply the formulation containing poloxamer of Zhang ‘417 to an aspacytarabine composition as taught by Gengrinovitch.
Applicant’s arguments regarding stirring duration, stirring intensity, order of addition, pH adjustment with NaOH, and precipitation caused by continuous stirring are also not persuasive because the rejected claims are directed to compositions, not methods of preparing the compositions. The rejected composition claims do not require a particular order of addition, a particular stirring time, a particular stirring intensity, or a particular process step involving NaOH. Therefore, Applicant’s arguments concerning particular preparation sequences or mixing conditions are not commensurate in scope with the pending composition claims. Applicant’s arguments concerning particular experimental failures under particular preparation sequences or mixing conditions do not establish the full scope of the claimed compositions exhibits unexpected results relative to the closest prior art. Evidence of unexpected results must have a nexus to the claimed invention and be reasonably commensurate in scope with the claims. Moreover, the fact that some formulation attempts may have failed does not establish that the claimed composition would have been nonobvious. Obviousness does not require absolute predictability. The proper inquiry is whether one of ordinary skill in the art would have had a reasonable expectation of success. Zhang ‘417 teaches poloxamer in an aqueous parenteral cytarabine-based composition, and Gengrinovitch teaches aspacytarabine hydrochloride as an aqueous intravenous formulation. These teachings would have provided a reasonable expectation of success for preparing an aqueous aspacytarabine composition comprising poloxamer.
With respect to the claims further reciting cyclodextrin, Carneiro et al. is relied upon for teaching cyclodextrin as known pharmaceutical excipients that form drug inclusion complexes and improve aqueous solubility, dissolution, bioavailability, physiochemical stability, and shelf-life. The current rejection does not require substitution of cyclodextrin for every excipient in the prior art. Instead, Carneiro et al. provides a known formulation technique for improving the solubility and stability of drug-containing compositions. One of ordinary skill in the art would have been motivated to include cyclodextrin in the aspacytarabine formulation to improve solubility and/or stability.
Conclusion
No claim is found to be allowable.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached Monday - Thursday 7:30 - 17:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SCARLETT GOON can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
Prosecution Insights