DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application 18/276,574 filed on August 9, 2023 is a 371 of PCT/US2022/015826 filed on February 9, 2022, which claims priority to, and the benefits of U.S. Provisional Application No.
63/147,625 filed on February 9, 2021.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on February 13, 2026, wherein claims 1, 22, 32 and 36 are amended; claims 2, 7-8, 10, 16, 19-21, 23-26, 29, 31, 33 and 35 are unchanged; and claims 3-6, 9, 11-15, 17-18, 27-28, 30, and 34 are cancelled.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 7-8, 10, 16, 19-26, 29, 31-33 and 35-36 are pending and under examination.
Claim Interpretation
The claimed term “about”, when construed in light of the special definition provides on page 7, line 13-14 of the specification shown below:
PNG
media_image1.png
46
736
media_image1.png
Greyscale
, is taken to include the broadest variation of ±10% of the value specified; therefore, the phrase “about … to about …” is taken to include the range, where the lower limit is calculated as the specified value minus 10% of that value, and the upper limit is calculated as the specified value plus 10% of that value. For example, if the range is “about 10 mg/kg to about 60 mg/kg per dose” (see claim 2):
Lower limit:
10
-
0.10
×
10
=
9
m
g
/
k
g
Upper limit:
60
+
0.10
×
60
=
66
m
g
/
k
g
, the range is reasonably interpreted as 9 mg/kg to 66 mg/kg.
The claimed phrase “for suspension” in claim 19 is reasonably construed to be an intended use of the oral powder, and that does not create a structural difference to the powder itself.
Action Summary
Claims 29 and 31-32 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in light of the claim amendments.
Claims 1-2, 7, 10, 16, 19-20, 26, and 35 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Smith et al. (Molecular genetics and metabolism, 2019. Vol. 126, 4: 406-412), as evidenced by Friciu et al. (PLoS One, 2016. Vol. 11(10): e0164577) are withdrawn in light of the claim amendments that added the limitation of “treating the subject with therapeutic radiation; and/or treating the subject with temozolomide (TMZ)”.
Claims 1-2, 26, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1; cited in the IDS filed on July 17, 2024) are withdrawn in light of the claim amendments that added the limitation of “treating the subject with therapeutic radiation; and/or treating the subject with temozolomide (TMZ)”.
Claims 1-2, 7-8, 10, 16, 19, 21, 26 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1; cited in the IDS filed on July 17, 2024) as applied to claims 1-2, 26 and 35 above, and further in view of Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”; cited in the IDS filed on July 17, 2024) are withdrawn in light of the claim amendments.
Claims 1-2, 7-8, 10, 16, 19-21, 26 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1; cited in the IDS filed on July 17, 2024), in view of Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”; cited in the IDS filed on July 17, 2024) as applied to claims 1-2, 7-8, 10, 16, 19, 21, 26 and 35 above, and further in view of Smith et al. (Molecular genetics and metabolism, 2019. Vol. 126, 4: 406-412), as evidenced by Friciu et al. (PLoS One, 2016. Vol. 11(10): e0164577) are withdrawn in light of the claim amendments.
Claims 1-2, 22-26, 29, 31-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable Penninger et al. (WO 2019/175328 A1; cited in the IDS filed on July 17, 2024) as applied to claims 1-2, 26 and 35 above, and further in view of Stupp et al. (The New England journal of medicine, 2005. Vol. 352, 10: 987-96) and Rabender et al. (The Journal of pharmacology and experimental therapeutics, 2018. Vol. 365, 3: 536-543; cited in the IDS filed on July 17, 2024) are maintain, but revisited and modified in light of the claim amendments that added the limitation of “treating the subject with therapeutic radiation; and/or treating the subject with temozolomide (TMZ)” to the independent claim 1.
Claims 1-2, 7-8, 10, 16, 19-20 and 35 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12, 22-23, 27-29 of copending Application No. 17/794,357 (reference application), as evidenced by Friciu et al. (PLoS One, 2016. Vol. 11(10): e0164577); claims 1-2, 7-8, 10 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 16-17 and 19-22 of copending Application No. 17/764,003 (reference application); claims 1, 2, 7-8, 22, 25-26, 29 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6 and 8-9 of copending Application No. 17/631,995 (reference application); and claims 1 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19, 21 and 36 of copending Application No. 17/059,887 (reference application) are withdrawn in light of the claim amendments.
Claims 1-2, 16, 19, 26, and 36 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6 and 8 of U.S. Patent No. 11,617,752 B2 (reference patent) in view of Penninger et al. (WO 2019/175328 A1; cited in the IDS filed on July 17, 2024) are withdrawn in light of the claim amendments.
Claims 1-2, 16, and 36 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 12,329,757 B2 (reference patent) are withdrawn in light of the claim amendments.
Claims 1-2, 10, and 36 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 12,257,252 B2 (reference patent) are withdrawn in light of the claim amendments.
Claims 1, 19 and 35 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 6 and 8 of U.S. Patent No. 11,752,154 B2 (reference patent) are withdrawn in light of the claim amendments.
Claims 1-2, and 35 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 and 6 of U.S. Patent No. 11,173,158 B2 (reference patent) are withdrawn in light of the claim amendments.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 22-26, 29, 31-33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1; cited in the IDS filed on July 17, 2024), in view of Stupp et al. (The New England journal of medicine, 2005. Vol. 352, 10: 987-96) and Rabender et al. (The Journal of pharmacology and experimental therapeutics, 2018. Vol. 365, 3: 536-543; cited in the IDS filed on July 17, 2024) (partially newly applied as necessitated by amendment).
Penninger et al. teaches tetrahydrobiopterin (BH4) slowed the growth of the tumors significantly in the mice with orthotopically injected E0771 breast cancer cells (see e.g., p. 42, “Example 7”); wherein BH4 (100 mg/kg) was therapeutically administered and carried out for 7 days (see e.g., p. 21, “Figure 6. Modulation of BH4 enhances anti-cancer immunity”, b; Figure. 6b). Penninger et al. further teaches a method of preventing or treating a cancer comprising increasing BH4 biological activity in the T cells (see e.g., p. 2, line 34 to p. 3, line 3); wherein said T cells are from a patient having or predisposed of developing a cancer (see e.g., claim 4; p. 4, line 15-16); wherein said cancer is selected from, inter alia, breast cancer and glioblastoma (see e.g., claim 5; p. 4, line 27-33). Penninger et al. further teaches the method comprising diagnosing the patient with the cancer or a predisposition thereto and then administering to the patient a BH4 biological activity agonist (see e.g., claim 7; p. 9, line 16-23); wherein the BH4 biological activity agonist is selected from, inter alia, tetrahydrobiopterin and sepiapterin (see e.g., claim 10; p. 10, line 22-24). Penninger et al. further teaches sapropterin, sepiapterin, or a pharmaceutical acceptable salt thereof for use in the treatment of a cancer in a patient (see e.g., page 3, line 9-12). Penninger et al. further teaches the BH4 agonist is formulated for administration in doses between 0.001 mg/kg body weight of a patient and 500 mg/kg, preferably between 0.1 mg/kg and 100 mg/kg, most preferred between 1 mg/kg and 40 mg/kg (see e.g., p. 17, line 6-9). Penninger et al. further teaches that according to preferred embodiments, the inventive therapy is combined with administration of a chemotherapeutic agent to the patient; and the chemotherapeutic agent may be selected from the group of, inter alia, alkylating agents (see e.g., p. 5, line 17-20). Penninger et al. further teaches the BH4 biological activity agonist can be used with or provided in a pharmaceutical preparation, preferably, the preparation is in the form of a formulation for systemic treatment, e.g., parenteral or oral; the preparation is intended for oral intake, preferably in the form of, inter alia, powders or drinking solutions (see e.g., p. 16, line 6-16). Penninger et al. further teaches the patient or a subject to be treated may be a mammal, preferably a human (see e.g., p. 6, line 28-30).
Penninger et al. does not teach therapeutic radiation and temozolomide.
Stupp et al. teaches the current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy (see e.g., abstract, “background” section). Stupp et al. further teaches in the trial that compares radiotherapy alone with radiotherapy plus temozolomide (see e.g., abstract, “background” section), the addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity (see e.g., abstract, “conclusions” section). Stupp et al. further teaches temozolomide, an oral alkylating agent, has demonstrated antitumor activity as a single agent in the treatment of recurrent glioma (see e.g., p. 988, left column, 2nd paragraph). Stupp et al. further teaches in the trial, patients with newly diagnosed and histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle)(see e.g., abstract, “methods”).
Rabender et al. teaches nitric oxide (NO) synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor sepiapterin (SP) inhibits tumor progression (see e.g., abstract). Rabender et al. further teaches MMTV-neu mice with spontaneous breast tumors treated with SP by oral gavage normalized vasculature and improved tumor oxygenation led to a greater than 2-fold increase in radiation-induced apoptosis compared with radiation or SP alone (see e.g., abstract). Rabender et al. further teaches the SP was given before radiation (see e.g., p. 539, left column, line 1-6). Rabender et al. further teaches the normalization of tumor vasculature allows for more efficient delivery of chemotherapeutic agents (see e.g., p. 539, “Pretreatment with SP Enhances Tumor Uptake of Doxorubicin and Increases Tumor Cell Apoptosis” section, line 1-4).
In the instant case, the difference between method of Penninger et al. and the claimed method is that the prior art only exemplify the method of treating breast cancer in a subject by administering tetrahydrobiopterin at 100 mg/kg to said subject in the working example; and does not teach treating the subject with therapeutic radiation and temozolomide. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the method of Penninger et al. by substituting tetrahydrobiopterin with sepiapterin as the BH4 biological activity agonist for treating glioblastoma as the cancer; and then combining said method with the method of Stupp et al. (radiotherapy plus temozolomide) that is useful for the same purpose of treating glioblastoma. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One would have been motivated to do so, because Penninger et al. teaches a list of BH4 biological activity agonists, including tetrahydrobiopterin and sepiapterin, and further teaches the cancer that can be treated by said BH4 biological activity agonist includes breast cancer and glioblastoma; and Stupp et al. teaches radiotherapy (reading on “therapeutic radiation”) plus temozolomide for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity; and therefore, each is taught by the prior art to be useful for the treatment of glioblastoma. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of sepiapterin as the BH4 biological activity agonist at an effective amount of 100 mg/kg to the subject having glioblastoma as the cancer would have successfully increase BH4 biological activity for the treatment of glioblastoma; and by combing the method of Penninger et al. (sepiapterin) with the method of Stupp et al. (radiotherapy plus temozolomide) that are useful separately for the treatment of glioblastoma would reasonably expected to be similarity useful when used together.
Moreover, alternative to the In re Kerkhoven analysis above, it would have been prima facie obvious to one of the ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the method of Penninger et al. by substituting tetrahydrobiopterin with sepiapterin as the BH4 biological activity agonist for treating glioblastoma as the cancer; and then further administering temozolomide as the alkylating agent and radiotherapy of Stupp et al. to the subject. One would have been motivated to do so, because Penninger et al. the method can be combined with administration of a chemotherapeutic agent, including alkylating agents; Stupp et al. teaches temozolomide is an alkylating agent, and temozolomide plus radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity; and Rabender et al. teaches sepiapterin enhances tumor radio- and chemosensitivities by promoting vascular normalization. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by administering the effective amount of sepiapterin of Penninger et al. with temozolomide and radiotherapy of Stupp et al. would have successfully treat glioblastoma as well as enhancing tumor radio- and chemosensitivities by promoting vascular normalization.
Regarding the limitation of “wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is about 10 mg/kg to about 60 mg/kg per dose” in claim 2, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin at an amount between 1 mg/kg and 40 mg/kg per dose. One would have been motivated to do so, because Penninger et al. teaches the BH4 biological activity agonist, including sepiapterin, is most preferably formulated for administration in doses between 1 mg/kg and 40 mg/kg. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the sepiapterin at an amount between 1 mg/kg and 40 mg/kg per dose in the method set forth above would have successfully increase BH4 biological activity for the treatment of glioblastoma.
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered during the duration of the therapeutic radiation” in claim 23, the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered prior to the therapeutic radiation” in claim 24, the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered subsequent to the therapeutic radiation” in claim 25, and the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered continuously concurrent to the therapeutic radiation” in claim 31, each of these instant situations is amenable to the type of analysis set forth in Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant process claims, one of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention by administering the sepiapterin of Penninger et al. during the duration of the radiotherapy taught by Stupp et al., prior to the radiotherapy taught by Stupp et al., subsequent to the radiotherapy taught by Stupp et al., or continuously concurrent to the radiotherapy taught by Stupp et al. in the method of Penninger et al., Stupp et al., and Rabender et al. set forth above for the treatment of glioblastoma.
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 6 days” in claim 26, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin for 7 days. One would have been motivated to do so, because Penninger et al. et al. teaches the BH4 biological activity agonist tetrahydrobiopterin was therapeutically administered and carried out for 7 days to slow the tumor growth in the animal model of breast cancer. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the sepiapterin for the same duration (7 days) as tetrahydrobiopterin would have successfully increase BH4 biological activity for treating glioblastoma, and that renders obvious the limitation of “at least 6 days” instantly claimed.
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered in 28-day cycles” in claim 32, and the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for six 28-day cycles” in claim 33, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin of Penninger et al. in 28-day cycle regimen or six 28-day cycle regimen taught by Stupp et al. through routine optimization. One would have been motivated to do so, because Stupp et al. teaches the standard treatment regimen for newly diagnosed glioblastoma includes six 28-day cycles of temozolomide. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected that by incorporating the sepiapterin of Penninger et al. into the treatment regimen taught by Stupp et al., which is the 28-day cycle regimen and six 28-day cycles, as a starting point would have successfully treated glioblastoma as well as enhancing tumor radio- and chemosensitivities by promoting vascular normalization.
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 14 days subsequent to the therapeutic radiation” in claim 29, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin of Penninger et al. with the 6 cycles of adjuvant temozolomide of Stupp et al. administered after the radiotherapy plus temozolomide. One would have been motivated to do so, because Rabender et al. teaches sepiapterin normalize vasculature, and normalization of tumor vasculature allows for more efficient delivery of chemotherapeutic agents; and Stupp et al. teaches adjuvant temozolomide was followed after the radiotherapy plus temozolomide, and the adjuvant temozolomide is administered at 150 to 200 mg per square meter for 5 days during each 28-day cycle. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of sepiapterin with the adjuvant temozolomide for 6 cycles would have successfully treat glioblastoma as well as enhancing the delivery of temozolomide. Please note 6 cycles of 5 day administration of adjuvant temozolomide, which when calculated by
6
×
5
=
30
, gives a total of 30 days of adjuvant temozolomide after the radiotherapy; and that renders obvious the limitation of “at least 14 days” instantly claimed.
Regarding the limitation of “wherein the subject is a human” in claim 35, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering to a human subject. One would have been motivated to do so, because Penninger et al. teaches the subject being treated is preferably a human; and Stupp et al. teaches the administration of radiotherapy plus temozolomide to patients in a clinical trial. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the sepiapterin, radiotherapy, and temozolomide can successfully treat a subject that is a human.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 7-8, 10, 16, 19, 21-26, 29, 31-33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1), in view of Stupp et al. (The New England journal of medicine, 2005. Vol. 352, 10: 987-96) and Rabender et al. (The Journal of pharmacology and experimental therapeutics, 2018. Vol. 365, 3: 536-543) as applied to claims 1-2, 22-26, 29, 31-33, 35-36 above, and further in view of Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”; cited in the IDS filed on July 17, 2024)(newly applied as necessitated by amendment).
The teachings of Penninger et al., Stupp et al., and Rabender et al. are set forth above and applied as before.
Penninger et al., Stupp et al., and Rabender et al. does not teach the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is administered once daily as claimed in claim 7; and administered twice daily as claimed in claim 8. Penninger et al., Stupp et al., and Rabender et al. also does not teach the effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, is administered with food as claimed in claim 10; and administered without food as claimed in claim 16. Penninger et al., Stupp et al., and Rabender et al. also does not teach the sepiapterin or a pharmaceutically acceptable salt thereof, is formulated as an oral powder for suspension as claimed in claim 19. Penninger et al., Stupp et al., and Rabender et al. also does not teach the sepiapterin or a pharmaceutically acceptable salt thereof, is administered as a powder suspended in water or juice as claimed in claim 21.
Smith#2 teaches a method of treating BH4-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, without food (see e.g., claim 1); the method also increases the sepiapterin plasma exposure, sepiapterin cerebrospinal fluid (CSF) and/or brain exposure in the subject receiving sepiapterin therapy (see e.g., claims 2-3); wherein the effective amount comprises a dose that is at least 20% lower than the dose sufficient to produce a maximum plasma concentration of at least 0.5 ng/mL in the subject with 1 hour of administration of sepiapterin, or a pharmaceutically acceptable salt thereof, with food (see e.g., claims 3 and 5-6). Smith#2 further teaches the term “BH4-related disorder” refers to any disease or disorder that may derive a therapeutic benefit from modulation of the level or activity of BH4 (see e.g., p. 5, line 34-35). Smith#2 further teaches patients may receive the pharmaceutical composition including sepiapterin once daily or twice daily during the treatment period (see e.g., p. 15, line 21-24). Smith#2 teaches sepiapterin, or a pharmaceutically acceptable salt thereof, can be used in the preparation of liquid formulations, such as in the form of a solution, suspension, or emulsion (see e.g., p. 11, line 11-12). Smith#2 further teaches formulations suitable for oral administration can consist of, inter alia, (b) powders; (c) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (d) suspensions in an appropriate liquid (see e.g., p. 11, line 12-16). Smith#2 further teaches the compound can be administered in a physiologically acceptable diluent in a pharmaceutical excipient, such as a sterile liquid or mixture of liquids, including water (see e.g., p. 11, line 33-35). Smith#2 further teaches in some embodiments, the pharmaceutical composition is a granular formulation that is dispersed in a pharmaceutically acceptable excipient, for example the composition can be mixed into water and ingested by a patient (e.g., over the course of 5 to 10 minutes) (see e.g., p. 12, line 4-7). Smith#2 further teaches as is known in the art, food can influence the absorption of compounds; absorption may be delayed, but not reduced, or the total amount of the drug absorbed may be reduced; the food effect may be due to slowing gastric or anterior intestine residence time, decreasing access of the compound to absorption sites, altering the dissolution rate of the compound, or altering the pH of the stomach; and because of these effects, it is important that a specific dosage schedule be established for drugs that should be administered apart from meals or with food (see e.g., p. 2, line 1-6).
Regarding the limitation of “wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is administered once daily” in claim 7, and the limitation of “wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is administered twice daily” in claim 8, each of these limitations are drawn to the dosing frequency of the sepiapterin or pharmaceutically acceptable salt thereof. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin once daily or twice daily. One would have been motivated to do so, because Smith#2 teaches administering the sepiapterin once daily or twice daily during the treatment period can successfully increase the sepiapterin plasma exposure, sepiapterin cerebrospinal fluid (CSF) and/or brain exposure in a subject receiving sepiapterin therapy for treating any disease or disorder that may derive a therapeutic benefit from modulation of the level or activity of BH4. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the sepiapterin of Penninger et al. once daily or twice daily in the method would successfully increase the sepiapterin plasma exposure, sepiapterin CSF and/or brain exposure for the treatment of glioblastoma.
Regarding the limitation of “wherein the effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, is administered with food” in claim 10, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the effective amount of sepiapterin with food through routine optimization. One would have motivated to do so, because Smith#2 teaches food can influence the absorption of compounds; and the effective amount of the sepiapterin administered without food comprises a dose that is at least 20% lower than the dose sufficient to produce a maximum plasma concentration of at least 0.5 ng/mL in the subject with 1 hour of administration of sepiapterin, or a pharmaceutically acceptable salt thereof, with food. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected by increasing the effective amount of the sepiapterin of Penninger et al. in the method, starting from the effective amount of 100 mg/kg taught by Penninger et al., when administered the sepiapterin with food would have successfully increases sepiapterin plasma exposure, the sepiapterin cerebrospinal fluid and/or brain exposure for the treatment of glioblastoma.
Regarding the limitation of “wherein the effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, is administered without food” in claim 16, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the effective amount of the sepiapterin without food. One would have been motivated to do so, because Smith#2 teaches the administration of sepiapterin without food increases sepiapterin plasma exposure, the sepiapterin cerebrospinal fluid and/or brain exposure in a subject receiving sepiapterin therapy. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by administering the sepiapterin of Penninger et al. without food in the method would have successfully increase the sepiapterin plasma exposure, the sepiapterin cerebrospinal fluid and/or brain exposure for the treatment of glioblastoma.
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof, is formulated as an oral powder for suspension” in claim 19, the recitation of “for suspension” in the claimed limitation simply express the intended use of the oral powder, and does not create a structural limitation to the oral powder itself. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin in the form of oral powder, as taught by Smith#2. One would have been motivated to do so, because Smith#2 teaches sepiapterin can be formulate into powders suitable for oral administration. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the sepiapterin formulated into oral powder can successfully administer said sepiapterin to the subject orally.
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof, is administered as a powder suspended in water or juice“ in claim 21, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., and Rabender et al. set forth above by administering the sepiapterin in the form of suspensions in water as the liquid, as taught by Smith#2. One would have been motivated to do so, because Smith#2 teaches sepiapterin can be formulate into powders or suspended in an appropriate liquid for oral administration; and acceptable pharmaceutical excipient includes water. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the sepiapterin formulated into suspensions in water can successfully administer said sepiapterin to the subject orally.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 1-2, 7-8, 10, 16, 19-26, 29, 31-33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1), in view of Stupp et al. (The New England journal of medicine, 2005. Vol. 352, 10: 987-96), Rabender et al. (The Journal of pharmacology and experimental therapeutics, 2018. Vol. 365, 3: 536-543), and Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”) as applied to claims 1-2, 7-8, 10, 16, 19, 21-26, 29, 31-33 and 35-36 above, and further in view of Smith et al. (Molecular genetics and metabolism, 2019. Vol. 126, 4: 406-412), as evidenced by Friciu et al. (PLoS One, 2016. Vol. 11(10): e0164577)(newly applied as necessitated by amendment).
The teachings of Penninger et al., Stupp et al., Rabender et al., and Smith#2 are set forth above and applied as before.
Penninger et al., Stupp et al., Rabender et al., and Smith#2 does not teach the sepiapterin or a pharmaceutically acceptable salt thereof, is administered as a suspension in a flavored suspending vehicle as claimed in claim 20.
Smith et al. teaches oral administration of CNSA-001, a novel formulation of sepiapterin, to healthy volunteers induced dose-related increase in plasma sepiapterin and tetrahydrobiopterin (BH4) following single doses and one week of daily dosing in a randomized, double-blind, placebo-controlled study (see e.g., p. 407, right column, “2.2. Study design”, 1st paragraph; abstract); wherein the increases in plasma BH4 were larger than those observed with equivalent doses of sapropterin dihydrochloride (see e.g., p. 412, left column, “5. Conclusions”). Smith et al. further teaches CNSA-001 was administered as an oral powder suspended in Medisca Oral Mix (see e.g., p. 407, right column, “2.2. Study design”, 1st paragraph). Please note the Medisca Oral Mix taught by Smith et al. is a flavored suspending vehicle, as evidenced by Friciu et al. (see e.g., page 2, “Introduction”, last paragraph).
Regarding the limitation of “wherein the sepiapterin or a pharmaceutically acceptable salt thereof, is administered as a suspension in a flavored suspending vehicle” in claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Penninger et al., Stupp et al., Rabender et al., and Smith#2 set forth above to administer the sepiapterin as a suspension in Medisca Oral Mix, which is a flavored suspending vehicle. One would have been motivated to do so, because Smith et al. teaches the CNSA-001, which is a formulation of sepiapterin administered as an oral powder suspended in Medisca Oral Mix, to the human subject can increases the plasma sepiapterin and tetrahydrobiopterin. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the sepiapterin in the form of CNSA-001, which is an oral powder suspended in Medisca Oral Mix as the flavored suspending vehicle, would have successfully increases the concentration of BH4 for the treatment of glioblastoma.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on February 13, 2026 with respect to the rejection of claims 1-2, 26, and 35 under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1); the rejection of claims 1-2, 7-8, 10, 16, 19, 21, 26 and 35 under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1) as applied to claims 1-2, 26 and 35 above, and further in view of Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”); the rejection of claims 1-2, 7-8, 10, 16, 19-21, 26 and 35 under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1), in view of Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”) as applied to claims 1-2, 7-8, 10, 16, 19, 21, 26 and 35 above, and further in view of Smith et al. (Molecular genetics and metabolism, 2019. Vol. 126, 4: 406-412), as evidenced by Friciu et al. (PLoS One, 2016. Vol. 11(10): e0164577); the rejection of claims 1-2, 7-8, 10, 16, 19-21, 26 and 35 under 35 U.S.C. 103 as being unpatentable over Penninger et al. (WO 2019/175328 A1), in view of Smith et al. (WO 2019/232130 A1; referred to herein as “Smith#2”) as applied to claims 1-2, 7-8, 10, 16, 19, 21, 26 and 35 above, and further in view of Smith et al. (Molecular genetics and metabolism, 2019. Vol. 126, 4: 406-412), as evidenced by Friciu et al. (PLoS One, 2016. Vol. 11(10): e0164577) have been fully considered, but they are moot in light of the claim amendments.
Applicant's arguments filed on February 13, 2026 with respect to the rejection of claims 1-2, 22-26, 29, 31-33, and 35-36 are under 35 U.S.C. 103 as being unpatentable Penninger et al. (WO 2019/175328 A1) as applied to claims 1-2, 26 and 35 above, and further in view of Stupp et al. (The New England journal of medicine, 2005. Vol. 352, 10: 987-96) and Rabender et al. (The Journal of pharmacology and experimental therapeutics, 2018. Vol. 365, 3: 536-543; cited in the IDS filed on July 17, 2024) have been fully considered but they are not persuasive for the reasons set forth below.
In the present case, Applicant amends claim 1 from the recitation of “[a] method of treating glioblastoma in a subject” to the recitation of “[a] method of therapeutic treatment of glioblastoma in a subject in need thereof”, and further added the limitation of “, wherein the method further comprises: (i) treating the subject with therapeutic radiation; and/or (ii) treating the subject with temozolomide (TMZ)”. It is noted that the limitation of “treating the subject with therapeutic radiation” is recited in previous claim 22, and the limitation of “treating the subject with temozolomide (TMZ)” is recited in previous claim 36. Each of these findings demonstrate the claim amendments changes the scope of the claims by incorporating the limitations recited in the previous dependent claims, and that necessitates a modification of the rejection on the record.
In Summary, Applicant argues Penninger et al. fails provide specific teaching of in vivo administration of sepiapterin to a subject having glioblastoma. Applicant further argues Rabender et al. only teaches the administration of sepiapterin in a MMTV-neu breast cancer model but fails to teach sepiapterin is effective for treating glioblastoma; and Stupp fails to teach sepiapterin. Applicant further argues the claimed invention demonstrate unexpected results by directing attention to Examples 1-3 and Figures 1-3 shown below:
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In response, applicant’s argument is not found persuasive. It may well be true Penninger et al. does not exemplify in vivo administration of sepiapterin to a subject having glioblastoma; However, according to MPEP 2123, “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)” and “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)”. In other words, the mere fact that Penninger et al. exemplified the in vivo administration of tetrahydrobiopterin (BH4) to a subject with breast cancer in the working examples (see e.g., p. 42, “Example 7”) does not explicitly exclude or discourage alternative methods. In fact, as stated in the rejection, Penninger et al. clearly teaches sepiapterin and tetrahydrobiopterin are both a BH4 biological activity agonist (see e.g., claim 10); sepiapterin or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer in a patient (see e.g., p. 3, line 9-12; claim 14); and the preferred cancer are, inter alia, breast cancer and glioblastoma (see e.g., p. 4, line 27-33). Therefore, one would have reasonably expected that sepiapterin and tetrahydrobiopterin are both a BH4 biological activity agonist that can be employed for treating breast cancer or glioblastoma in a patient, in the absence of evidence to the contrary.
Applicant’s argument with respect to Rabender et al., and Stupp et al. are against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is respectfully noted that the rejection on the record in form using the combination of Penninger et al., Rabender et al., and Stupp et al. rather than each prior art separately. It is respectfully noted that the rejection on the record uses Penninger et al. to teach the administration of an effective amount of sepiapterin as a BH4 biological activity agonist for treating glioblastoma, rather than Rabender et al. and Stupp et al. The rejection on the record further rely on Stupp et al. to teach temozolomide plus radiotherapy for treating glioblastoma, and Rabender et al. to teach the administration of tetrahydrobiopterin precursor sepiapterin inhibits tumor progression by normalizing tumor vasculature for more efficient delivery of chemotherapeutic agents, and increase radiation-induced apoptosis. Therefore, applicant’s argument against each reference individually is not found persuasive.
Additionally, Applicant argues unexpected results are demonstrated in Example 1-3 and Figure 1-2; However, applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention.
According to page 38-39 of the specification (see “Example 1”), staring on Day 6, sepiapterin (SP) was orally administered for either 6 days (10 mg/kg sepiapterin) or daily (1 mg/kg sepiapterin) until end of experiment (60 days); and radiation (IR) with 3D treatment planning and delivery was started on Day 13, ending on Day 17; and the results of Example 1 are shown in Figures 1-4. As disclosed therein, Figure 1 shows “[t]he difference between the 10 mg/kg for 6d group and the IR alone group did not achieve statistical significance” (see e.g., p. 38, line 31-32), and the 1 mg/kg daily dose of sepiapterin in combination with radiation was the only treatment group that showed statistical significance (see e.g., see e.g., p. 38, line 32-34); and Figure 2 shows the group treated with 10 mg/kg daily dose of sepiapterin with radiation has an increased survival rate when compared to the group treated with radiation or 10 mg/kg daily dose of sepiapterin alone. According to page 39 of the specification (see “Example 2”), starting on Day 7, mice with orthotopic GL261 tumors were treated with “60 mg/kg temozolomide for 5 days +/- 10 mg/kg SP given orally from day 7 until the end of the study”; and “mice receiving TMZ+SP had improved survival over mice receiving TMZ alone”, as shown in Figure 3. According to page 39-40 (see “Example 3”), “(1) 8 mice were irradiated (IR) with 10 Gy total dose, divided into three fractions with a "rest" day in between fractions, covering about a 1 mm square over the center of the head; (2) 8 mice were similarly irradiated, and also treated with 10 mg/kg/day sepiapterin (SP), administered as oral gavage, starting on day 1 of IR to 6 days beyond last radiation fraction (i.e. 11 days total); (3) 8 mice were untreated naïve”, and the administration of SP increased Discrimination Index compared with irradiated-only group, as shown in Figure 3.
In contrast, instant claim 1 recites “[a] method of therapeutic treatment of glioblastoma in a subject in need thereof, the method comprising administering to the subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof, wherein the method further comprises: (i) treating the subject with therapeutic radiation; and/or (ii) treating the subject with temozolomide (TMZ)”. In other words, the present claim(s) encompass administering any effective amount of sepiapterin or a pharmaceutically acceptable salt thereof, and further administering therapeutic radiation and/or temozolomide for therapeutically treating glioblastoma. It is noted that Applicant only exemplified unexpected result using a specific combination species, i.e., (i) 10 mg/kg daily of oral sepiapterin from Day 6 to Day 60 in combination with radiation (5fx of 2 Gy) from Day 13 to Day 17 (see Example 1); (ii) 10 mg/kg of oral sepiapterin from day 7 until the end of the study in combination with 60 mg/kg temozolomide for 5 days (see Example 2); and (iii) 10 mg/kg/day of oral sepiapterin from day 1 of radiation to 6 days beyond last radiation fraction (11 days total) (see Example 3). These three combination species addressed above does not provide adequate basis for concluding that similar results would be obtained for other combination species composed of different effective amount of sepiapterin or a pharmaceutically acceptable slat thereof, and different effective amount of temozolomide. It also does not provide adequate basis for concluding that similar results would be obtained for a different combination species that administer sepiapterin, radiation and temozolomide together. The specification only exemplify a single species of administration, i.e., oral administration, and that does not provide adequate basis for concluding that similar results would be obtained for any other administration species, such as intravenous or topical.
According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. In the present case, Examples 1-3 do not exemplify any other effective amount of sepiapterin or a pharmaceutically acceptable slat thereof and any other effective amount of temozolomide with or without radiation as broadly encompass by the claim(s). Furthermore, the disclosure only exemplifies oral administration of sepiapterin, and that are not commensurate in scope to encompass any administration (e.g., intravenous). Each of these finding demonstrates that applicant’s assertion of unexpected results is not commensurate in scope with the claim invention, thus, the argument is not persuasive.
Furthermore, the unexpected results upon which applicant relies would have ben expected. According to Rabender et al. (The Journal of pharmacology and experimental therapeutics, 2018. Vol. 365, 3: 536-543; cited in the IDS filed on July 17, 2024), tetrahydrobiopterin precursor sepiapterin can inhibits tumor progression by restoring nitric oxide synthase coupling (see e.g., abstract). Rabender et al. further teaches oral sepiapterin increases radiation-induced apoptosis compared with radiation or SP alone by promoting vascular normalization and improving tumor oxygenation (see e.g., abstract); and normalizing tumor vasculature allows for more efficient delivery of chemotherapeutic agents (see e.g., p. 539, “Pretreatment with SP Enhances Tumor Uptake of Doxorubicin and Increases Tumor Cell Apoptosis” section, line 1-4). In other words, sepiapterin is a tetrahydrobiopterin precursor known to increases apoptosis induced by therapeutic radiation, and known to increase efficiency for delivering chemotherapeutic agents. Therefore, one of ordinary skill in the art would have reasonably expected that by combining sepiapterin with therapeutic radiation would have successfully increases apoptosis, and combining sepiapterin with chemotherapeutic agents would allow more efficient delivery, in the absence of evidence to the contrary.
Therefore, the rejection on the record has been maintained, but revisited and modify in light of the claim amendments. Since the amendment changes the scope of the dependent claims, it necessitates a new ground of rejection for the reasons set forth herein.
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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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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