DETAILED ACTION
Claims 1-14, submitted on 13 June 2023, are pending in the application and subject to examination in the instant Office 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 .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 8 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the suppression of proliferation of a diffuse intrinsic pontine glioma (DIPG) cell through administration of an alkylating hexitol derivative, does not reasonably provide enablement for a method further comprising administering a therapeutically effective quantity of an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Breadth of the Claims
Claim 8 recites “the method further comprises administering a therapeutically effective quantity of an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect.” Claim 8 identifies the compounds being used by a broad biological function in that the agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect in which it is unclear what compound the claim is referencing and could be interpreted to be the compound of claim 1 or an altogether different compound. Additionally, the description fails to provide any direction of what compounds are included in the genre. As such, the claim 8 fails to explicitly define what compounds fall within the scope of the claim.
Nature of the Invention
The nature of the invention is within the pharmaceutical arts with regards to suppressing proliferation of a diffuse intrinsic pontine glioma (DIPG) cell with an alkylating hexitol derivative.
State of the Prior Art
The state of the prior art is what one skilled in the art would have known, at the
time the application was filed, about the subject matter to which the claimed invention
pertains. The relative skill of those in the art refers to the skill of those in the art at the
time the application was filed. See MPEP 2164.05(b). See Pac. Bioscience of Cal., Inc.
v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir.
2021).
The state of the prior art provides evidence for the degree of predictability in the
art and is related to the amount of direction or guidance needed in the specification as
filed to meet the enablement requirement. The state of the prior art is also related to the
need for working examples in the specification. See MPEP 2165.05(a).
The prior art teaches wherein VAL-083, dianhydrogalactitol, is a bifunctional alkylating agent causing interstrand DNA crosslinks at N7 of guanine leading to cell cycle arrest in the S/G2 phase and cell death due to DNA double strand breaks (Background), as taught by Bacha (2016) ("Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors." Cancer Research. Vol. 76. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2016.), henceforth known as Bacha (2016).
The prior art also teaches wherein the Wee1 tyrosine kinase inhibitor, MK-1775, puts cells into cell cycle arrest at the S/G2 phase as Wee1 is a critical driver of G2-M cell cycle progression (pg. 352, Section “Introduction”, Left Col., 2nd paragraph) as taught by Mueller ("Targeting Wee1 for the treatment of pediatric high-grade gliomas." Neuro-oncology 16.3 (2014): 352-360.).
What the prior art does not appear to teach is a commonly accepted definition for “an agent that requires malignant cells to be in the S/G2 phase of the cell cycle”. Additionally, it’s unclear if the agent that is meant to be the alkylating hexitol derivative or, as the prior art does teach, is an altogether different compound which could include the compounds cisplatin (pg. 3, Section “Mechanisms of cisplatin in cell death…”, Right Col., 2nd paragraph), paclitaxel (pg. 4, Section “Paclitaxel mechanism of action”, Left Col., 1st paragraph), and doxorubicin (pg. 9, Section “Mechanisms of doxorubicin in cell death”, Right Col., 1st paragraph), as taught by Mollaei ("Chemotherapeutic drugs: Cell death-and resistance-related signaling pathways. Are they really as smart as the tumor cells?." Translational oncology 14.5 (2021): 101056.).
Level of Skill in the Art
The person of ordinary skill in the art is a person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the
level of ordinary skill in the art may include: (A) "type of problems encountered in the
art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are
made;" (D) "sophistication of the technology; and" (E) "educational level of active
workers in the field. In a given case, every factor may not be present, and one or more
factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121
(Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955,
962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil
Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP 2141.03 (I).
The invention described pertains to the medical or pharmaceutical arts. One of
ordinary skill would be trained in pharmacology, biochemistry, medicine, or a related art
field with a Ph. D or other advanced degree in these or other related fields.
Level of Predictability in the Art
The amount of guidance or direction needed to enable the invention is inversely
related to the amount of knowledge in the state of the art as well as the predictability of
the art. In re Fisher, 427, F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount
of guidance or direction” refers to that information in the application, as originally filed,
that teaches exactly how to make or use the invention. The more that is known in the
prior art about the nature of the invention, how to make, and how to use the invention,
and the more predictable the art is, the less information needs to be explicitly stated in
the specification. In contrast, if little is known in the prior art about the nature of the
invention and the art in unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. The scope of the required
enablement varies inversely with the degree of predictability involved, but even in
unpredictable art, a disclosure of every operable species is not required. A single
embodiment may provide broad enablement in cases involving predictable factors, such
as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ
122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA
1971). However, in applications directed to inventions in arts where the results are
unpredictable, the disclosure of a single species usually does not provide an adequate
basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA
1938). In cases involving unpredictable factors, such as most chemical reactions and
physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166
USPQ 18, 24 (CCPA 1970). See MPEP 2164.03. The applicant would need to provide
more objective evidence to support the enablement of the aforementioned claims to
contrast the unpredictability of the subject matter art.
There is unpredictability in the field of endeavor in regards to the currently claimed method of suppressing proliferation in a diffuse intrinsic pontine glioma with an alkylating hexitol derivative wherein the method further comprises administering a therapeutically effective quantity of an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect. There is unpredictability in the pharmaceutical arts with the practice of combining chemotherapeutic agents. One skilled in the art would know that there are challenges associated with designing drug combination for chemotherapy such as drug resistance and a compounds ability to pass the blood-brain barrier.
Amount of Direction Provided by the Inventor
The amount of direction provided by the inventor is correlated by the nature of
the unpredictability of the art. Given the context and scope of the claims mentioned
above, the inventor failed to provide the necessary amount of direction for one skilled in
the art to adequately use the invention across all suggested utility in the broadly stated
disease and disorders disclosed above. (See: Section (A) Breadth of the Claims).
The Applicant has provided guidance on dianhydrogalactitol monotherapy and in combinatory treatment with dianhydrogalactitol and the Wee1 inhibitor, AZD1775, in an in vitro proliferation/viability study using DIPG biopsy-derived tumor cells as found in the instant specification on page 17, lines 8-27. Applicant has further provided guidance on dianhydrogalactitol monotherapy and in combinatory treatment with dianhydrogalactitol and the Wee1 inhibitor, AZD1775, in an in vivo orthotopic engraftment model of pediatric DIPG (SF8628) as found in the instant specification on page 17, lines 28-33.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
As previously stated, the amount of experimentation depends on the art, the
predictability of the art, and the direction provided by the inventor. For one skilled in the
art to practice the invention as disclosed, the artisan trying to practice Applicant’s
claimed invention would be required to undertake unduly burdensome activities
including:
Experimentation to demonstrate in vitro application of dianhydrogalactitol and an agent that meets the limitations of instant claim 8.
Experimentation to show the dosage and frequency required to suppress the proliferation of a DIPG cell through administration of dianhydrogalactitol and an agent that meets the limitations of instant claim 8.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 8 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically, claim 8 recites the limitation “the method further comprises administering a therapeutically effective quantity of an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect” for which the specification does not provide an adequate written description to convey that the inventors were in possession of the full scope of the claimed invention.
The instant specification does not teach the use of dianhydrogalactitol in combination with an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect. In fact, the instant specification only makes note of an agent that requires malignant cell to in the S/G2 phase of the cell cycle for its maximum therapeutic effect in the “Other Agents” section of the specification where it states that “agents that require cancer cells to be in S/G2-phase for maximum effect, including topoisomerase inhibitors, can have synergistic effect with VAL-083”. It’s widely known that the pharmaceutical arts are unpredictable and as such, there would be uncertainty in the combination of pharmaceutical agents without experimentation due to the risk of potential incompatibility.
Additionally, the Examples provided by the Applicant in the instant specification (pages 16-19), are drawn to dianhydrogalactitol monotherapy and in combinatory treatment with dianhydrogalactitol and the Wee1 inhibitor, AZD1775, in an in vitro proliferation/viability study using DIPG biopsy-derived tumor cells as found in the instant specification on page 17, lines 8-27 and dianhydrogalactitol monotherapy and in combinatory treatment with dianhydrogalactitol and the Wee1 inhibitor, AZD1775, in an in vivo orthotopic engraftment model of pediatric DIPG (SF8628) as found in the instant specification on page 17, lines 28-33. The Applicant provided no experimentation on the combinatory treatment with dianhydrogalactitol with an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for its maximum therapeutic effect.
Regarding the requirement for adequate written description of chemical entities, Applicant's attention is directed to the MPEP §2163. In particular, Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), holds that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, "not a mere wish or plain for obtaining the claimed chemical invention.” Eli Lilly, 119 F.3d at 1566. The Federal Circuit has adopted the standard set forth in the Patent and Trademark Office ("PTO") Guidelines for Examination of Patent Applications under the 35 U.S.C. 112.1 "Written Description" Requirement ("Guidelines"), 66 Fed. Reg. 1099 (Jan. 5, 2001), which state that the written description requirement can be met by "showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics," including, inter aria, "functional characteristics when coupled with a known or disclosed correlation between function and structure..." Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 316, 1324-25 (Fed. Cir. 2002) (quoting Guidelines, 66 Fed. Reg. at 1106 (emphasis added)).
For the above reasons expressed above, the recitation of “an agent that requires malignant cell to in the S/G2 phase of the cell cycle for its maximum therapeutic effect” is not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the instantly claimed invention. Additionally, as the functional property of the genus of compounds does not permit one to envisage which compounds would have that desired biological function.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3 and 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chiuten et al. ("Clinical trials with the hexitol derivatives in the US." Cancer 47.3 (1981): 442-451.).
Chiuten discloses a method of using an alkylating hexitol derivative (Abstract; pg. 442, Section “Mechanism of Action”, Right Col., 1st paragraph), wherein the alkylating hexitol derivative is dianhydrogalactitol (DAG) (Abstract), for the treatment of brain tumors (pg. 444, Section “Human Pharmacology”, Left Col., 4th paragraph; pg. 445, Table 4). Chiuten also discloses a study conducted wherein the administration is done in vivo (pg. 448, Section “Antitumor spectrum”, Left Col., 7th paragraph).
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 and 8 are rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by Bacha et al. (WO 2017/042634 A2).
Bacha discloses a method of suppressing cancer cell proliferation (paragraph 0635; Figure 5) by administering to the cancer cell an alkylating hexitol derivative (paragraphs 0579 and 0634), wherein the cancer can be childhood glioblastoma (paragraph 0139). Bacha also discloses wherein the alkylating hexitol derivative is dianhydrogalactitol (Abstract; paragraphs 0091 and 0138; Claims 1 and 5) and further wherein dianhydrogalactitol leads to cell cycle arrest at S and G2 phase (paragraph 0635). Bacha continues to teach wherein dianhydrogalactitol can be administered in a combinatory treatment (paragraph 0146). While Bacha does not explicitly teach wherein the cancer cell is in a human subject, or wherein the subject is a pediatric patient, it can be inferred that the invention is designed with the intention of administration to a human in vivo, by the recitation of paragraph 0140 which states “use of pediatric doses for elderly patients, altered doses for obese patients; exploitation of co-morbid disease conditions such as diabetes, cirrhosis, or other conditions that may uniquely exploit a feature of the compound”.
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.
Claims 1-14 are rejected under 35 U.S.C. 103 as being obvious over Bacha et al. (WO 2017/042634 A2) in view of Chiuten et al. ("Clinical trials with the hexitol derivatives in the US." Cancer 47.3 (1981): 442-451.), Bacha et al. ("Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors." Cancer Research. Vol. 76. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2016.), henceforth known as Bacha (2016), and Mueller et al. ("Targeting Wee1 for the treatment of pediatric high-grade gliomas." Neuro-oncology 16.3 (2014): 352-360.), as evidenced by Bridges et al. ("MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells." Clinical cancer research 17.17 (2011): 5638-5648.).
The teachings of Bacha and Chiuten are applied to claims 1-5 and 8, as discussed in the 102 rejections above, and the teachings of these references are incorporated herein.
While Bacha teaches the use of an alkylating hexitol derivative, wherein the alkylating hexitol derivative is dianhydrogalactitol, in the treatment of childhood glioblastoma. It does not teach wherein the administration is conducted in vivo or wherein the cell proliferation to be suppressed is a diffuse intrinsic pontine glioma (DIPG) cell. Further, it does not teach wherein the method further comprises administering a therapeutically effective amount of a Wee1 tyrosine kinase inhibitor.
However, with respect to claim 6, Bacha (2016) cures the deficiency of in vivo human administration by teaching wherein dianhydrogalactitol (VAL-083) has demonstrated activity in glioblastoma independent of MGMT expression in vitro and in vivo (Abstract) and further cites clinical trials showing activity against a range of brain tumor types to include high-grade gliomas (Background). Hence, it would have been prima facie obvious for an ordinary skilled artisan to combine the teachings of Bacha with the teachings of Chiuten and Bacha (2016) to administer VAL-083 to a patient diagnosed with a different brain stem tumor, wherein that cancer is diffuse intrinsic pontine glioma, to suppress cell proliferation. Said ordinary skilled artisan would have had a reasonable expectation of success because Chiuten teaches wherein DAG is noted to accumulate in brain tumors to a higher degree than in the intact white matter (pg. 444, Section “Human pharmacology”, Left Col., 4th paragraph) and further because Bacha (2016) teaches wherein VAL-083 inhibits the self-renewal of the pediatric glioblastoma multiforme cancer stem cell line (SF188) by ~90% (Figure 3). Thus, it would have been prima facie obvious for a skilled artisan, prior to the effective filing date of the instantly claimed invention, to combine the teachings of Bacha with the teachings of Chiuten and Bacha (2016), to arrive at the instantly claimed invention. This also reads on instant claim 7 which recites the limitation “wherein the administering is done in vivo in a human subject”.
Regarding claim 9, Bacha teaches wherein dianhydrogalactitol can be administered in a combinatory treatment (paragraph 0146). However, this reference does not teach wherein that combinatory treatment includes a Wee1 tyrosine kinase inhibitor. Mueller cures this deficiency by teaching a method of administering a Wee1 inhibitor, MK-1775, which is also known as AZD1775, in the treatment of pediatric high-grade gliomas (pg. 352, Section “Background”, 1st paragraph). Additionally, as evidenced by Bridges, which teaches MK-1775 in the treatment of human tumor cells (Abstract), MK-1775 administration is optimally scheduled by administering the chemotherapeutic drug followed by subsequent treatment with MK-1775 (pg. 5641, Section “MK-1775 radiosensitizes human tumor cells…”, Left Col., 1st paragraph). For the above reasons, it would have been prima facie obvious for a person having ordinary skill in the art to combine the teachings of Bacha with the teachings of Chiuten, Bacha (2016), and Mueller, as evidenced by Bridges, to administer VAL-083 to a patient diagnosed with a different brain stem tumor, wherein that cancer is diffuse intrinsic pontine glioma, to suppress cell proliferation and further to administer a therapeutically effective quantity of a Wee1 tyrosine kinase inhibitor, wherein the Wee1 tyrosine kinase inhibitor is AZD1775. An ordinary skilled artisan would have had a reasonable expectation of success because Mueller discloses that Wee1 is significantly upregulated in pediatric gliomas (pg. 357, Section “Discussion”, Right Col., 1st paragraph). Thus, it would have been prima facie obvious for a skilled artisan, prior to the effective filing date of the instantly claimed invention, to combine the teachings of Bacha with the teachings of Chiuten, Bacha (2016), and Mueller as evidenced by Bridges, to arrive at the instantly claimed invention. This also reads on instant claim 10, which recites the limitation wherein the Wee1 tyrosine kinase inhibitor is AZD1775 and instant claim 12, which recites that the alkylating hexitol derivative and the Wee1 inhibitor are administered in any order.
Regarding claim 11, Bacha (2016) teaches wherein Val-083 retained cytotoxic activity in the presence of p53 mutations (Section “Conclusion”).
With respect to claim 13, while Mueller does not teach the instant combination, this reference does teach a study in which tumor-bearing mice received MK-1775 in combination with radiation therapy wherein the radiation was administered between doses of MK-1775 (pg. 354, Section “In vivo Treatment of Tumor-bearing…”, Right Col., 1st paragraph). Mueller also discloses where MK-1775 is the only Wee1 kinase inhibitor in clinical trials in combination with conventional chemotherapy (pg. 353, Section “Introduction”, Left Col., 3rd paragraph). Further, Mueller teaches wherein treatments were initiated when intracerebral tumors entered the log-phase growth as indicated by tumor bioluminescence monitoring (pg. 354, Section “In vivo Treatment of Tumor-bearing…”, Right Col., 1st paragraph). It would have been prima facie obvious to one skilled in the art to administer the combination of an alkylating hexitol derivative with the Wee1 tyrosine kinase inhibitor on the same or different days as determined through routine optimization and experimentation to determine the optimal administration schedule of both compounds for a subject in need thereof. This also reads on the limitations of instant claim 14 which recite “wherein the alkylating hexitol derivative and the inhibitor of Wee1 tyrosine kinase are administered on the same days”.
The applied reference has a common assignee and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Chiuten et al. ("Clinical trials with the hexitol derivatives in the US." Cancer 47.3 (1981): 442-451.) in view of Bacha et al. ("Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors." Cancer Research. Vol. 76. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2016.), henceforth known as Bacha (2016)) and Mueller et al. ("Targeting Wee1 for the treatment of pediatric high-grade gliomas." Neuro-oncology 16.3 (2014): 352-360.), as evidenced by Bridges et al. ("MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells." Clinical cancer research 17.17 (2011): 5638-5648.).
Chiuten discloses a method of using an alkylating hexitol derivative (Abstract; pg. 442, Section “Mechanism of Action”, Right Col., 1st paragraph), wherein the alkylating hexitol derivative is dianhydrogalactitol (DAG) (Abstract), for the treatment of brain tumors (pg. 444, Section “Human Pharmacology”, Left Col., 4th paragraph; pg. 445, Table 4). Chiuten also discloses a study conducted wherein the administration is done in vivo (pg. 448, Section “Antitumor spectrum”, Left Col., 7th paragraph). Which also reads on instant claim 2, which recites the limitation “wherein the alkylating hexitol derivative is dianhydrogalactitol” and instant claim 3, which recites the limitation “wherein the alkylating hexitol derivative is dianhydrogalactitol”.
Chiuten does not teach wherein the brain tumor is a DIPG cell in a human subject. However, Bacha (2016) cures the deficiency of in vivo human administration by teaching wherein dianhydrogalactitol (VAL-083) has demonstrated activity in glioblastoma independent of MGMT expression in vitro and in vivo (Abstract) and further cites clinical trials showing activity against a range of brain tumor types to include high-grade gliomas (Background). Therefore, it would have been prima facie obvious for an ordinary skilled artisan to combine the teachings of Chiuten with the teachings of Bacha (2016) to administer VAL-083 to a patient diagnosed with a different brain stem tumor, wherein that cancer is diffuse intrinsic pontine glioma, to suppress cell proliferation in a pediatric patient. Said ordinary skilled artisan would have had a reasonable expectation of success because Chiuten teaches wherein DAG is noted to accumulate in brain tumors to a higher degree than in the intact white matter (pg. 444, Section “Human pharmacology”, Left Col., 4th paragraph) and further because Bacha (2016) teaches wherein VAL-083 inhibits the self-renewal of the pediatric glioblastoma multiforme cancer stem cell line (SF188) by ~90% (Figure 3). Thus, it would have been prima facie obvious for a skilled artisan, prior to the effective filing date of the instantly claimed invention, to combine the teachings of Chiuten with the teachings of Bacha (2016), to arrive at the instantly claimed invention. This also reads on instant claim 5, which recites the limitation “wherein the human subject is a pediatric patient”; instant claim 6, which recites the limitation “wherein the administration is done in vivo”; and instant claim 7, which recites the limitation “wherein the administration is done in vivo in a human subject by administering a therapeutically effective quantity of the alkylating hexitol derivative to the human subject”.
With regards to claim 8, Bacha (2016) teaches wherein VAL-083 is a bifunctional alkylating agent causing interstrand DNA crosslinks at N7 of guanine leading to cell cycle arrest in the S/G2 phase and cell death due to DNA double strand breaks (Background).
With regards to claim 9, Bacha (2016) teaches that VAL-083 was investigated in a number of NCI-sponsored clinical trials, both as a stand-alone therapy and in combination with other chemotherapeutic regimens (Background). Bacha (2016) does not teach wherein the other chemotherapeutic regimens are an inhibitor of Wee1 tyrosine kinase. Mueller cures this deficiency by teaching a method of administering a Wee1 inhibitor, MK-1775, which is also known as AZD1775, in the treatment of pediatric high-grade gliomas (pg. 352, Section “Background”, 1st paragraph). Additionally, as evidenced by Bridges, which teaches MK-1775 in the treatment of human tumor cells (Abstract), MK-1775 administration is optimally scheduled by administering the chemotherapeutic drug followed by subsequent treatment with MK-1775 (pg. 5641, Section “MK-1775 radiosensitizes human tumor cells…”, Left Col., 1st paragraph). For the above reasons, it would have been prima facie obvious for a person having ordinary skill in the art to combine the teachings of Chiuten with the teachings of Bacha (2016) and Mueller, as evidenced by Bridges, to administer VAL-083 to a patient diagnosed with a different brain stem tumor, wherein that cancer is diffuse intrinsic pontine glioma, to suppress cell proliferation and further to administer a therapeutically effective quantity of a Wee1 tyrosine kinase inhibitor, wherein the Wee1 tyrosine kinase inhibitor is AZD1775. An ordinary skilled artisan would have had a reasonable expectation of success because Mueller discloses that Wee1 is significantly upregulated in pediatric gliomas (pg. 357, Section “Discussion”, Right Col., 1st paragraph). Thus, it would have been prima facie obvious for a skilled artisan, prior to the effective filing date of the instantly claimed invention, to combine the teachings of Chiuten with the teachings of Bacha (2016) and Mueller as evidenced by Bridges, to arrive at the instantly claimed invention. This also reads on instant claim 10, which recites the limitation wherein the Wee1 tyrosine kinase inhibitor is AZD1775 and instant claim 12, which recites that the alkylating hexitol derivative and the Wee1 inhibitor are administered in any order.
Regarding claim 11, Bacha (2016) teaches wherein Val-083 retained cytotoxic activity in the presence of p53 mutations (Section “Conclusion”).
With respect to claim 13, while Mueller does not teach the instant combination, this reference does teach a study in which tumor-bearing mice received MK-1775 in combination with radiation therapy wherein the radiation was administered between doses of MK-1775 (pg. 354, Section “In vivo Treatment of Tumor-bearing…”, Right Col., 1st paragraph). Mueller also discloses where MK-1775 is the only Wee1 kinase inhibitor in clinical trials in combination with conventional chemotherapy (pg. 353, Section “Introduction”, Left Col., 3rd paragraph). Further, Mueller teaches wherein treatments were initiated when intracerebral tumors entered the log-phase growth as indicated by tumor bioluminescence monitoring (pg. 354, Section “In vivo Treatment of Tumor-bearing…”, Right Col., 1st paragraph). It would have been prima facie obvious to one skilled in the art to administer the combination of an alkylating hexitol derivative with the Wee1 tyrosine kinase inhibitor on the same or different days as determined through routine optimization and experimentation to determine the optimal administration schedule of both compounds for a subject in need thereof. This also reads on the limitations of instant claim 14 which recite “wherein the alkylating hexitol derivative and the inhibitor of Wee1 tyrosine kinase are administered on the same days”.
The applied reference has a common assignee and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
Claims 1-14 are rejected under 35 U.S.C. 103 as being obvious over Bacha et al. (WO 2017/042634 A2) in view of Bacha et al. ("Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors." Cancer Research. Vol. 76. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2016.), henceforth known as Bacha (2016)) and Mueller et al. ("Targeting Wee1 for the treatment of pediatric high-grade gliomas." Neuro-oncology 16.3 (2014): 352-360.), as evidenced by Bridges et al. ("MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells." Clinical cancer research 17.17 (2011): 5638-5648.).
Bacha discloses a method of suppressing cancer cell proliferation (paragraph 0635; Figure 5) by administering to the cancer cell an alkylating hexitol derivative (paragraphs 0579 and 0634), wherein the cancer can be childhood glioblastoma (paragraph 0139). Bacha also discloses wherein the alkylating hexitol derivative is dianhydrogalactitol (Abstract; paragraphs 0091 and 0138; Claims 1 and 5) and further wherein dianhydrogalactitol leads to cell cycle arrest at S and G2 phase (paragraph 0635). Bacha continues to teach wherein dianhydrogalactitol can be administered in a combinatory treatment (paragraph 0146). This also reads on instant claims 2-3 and instant claim 8.
Bacha does not teach wherein the brain tumor is a DIPG cell in a human subject. However, Bacha (2016) cures the deficiency by teaching in vivo human administration wherein dianhydrogalactitol (VAL-083) has demonstrated activity in glioblastoma independent of MGMT expression in vitro and in vivo (Abstract) and further cites clinical trials showing activity against a range of brain tumor types to include high-grade gliomas (Background). Therefore, it would have been prima facie obvious for an ordinary skilled artisan to combine the teachings of Bacha with the teachings of Bacha (2016) to administer VAL-083 to a patient diagnosed with a different brain stem tumor, wherein that cancer is diffuse intrinsic pontine glioma, to suppress cell proliferation. Said ordinary skilled artisan would have had a reasonable expectation of success because Bacha (2016) teaches wherein VAL-083 inhibits the self-renewal of the pediatric glioblastoma multiforme cancer stem cell line (SF188) by ~90% (Figure 3). Thus, it would have been prima facie obvious for a skilled artisan, prior to the effective filing date of the instantly claimed invention, to combine the teachings of Bacha with the teachings of Bacha (2016), to arrive at the instantly claimed invention. This also reads on instant claims 4-7.
With regards to claim 9, Bacha (2016) teaches that VAL-083 was investigated in a number of NCI-sponsored clinical trials, both as a stand-alone therapy and in combination with other chemotherapeutic regimens (Background). Bacha (2016) does not teach wherein the other chemotherapeutic regimens are an inhibitor of Wee1 tyrosine kinase. Mueller cures this deficiency by teaching a method of administering a Wee1 inhibitor, MK-1775, which is also known as AZD1775, in the treatment of pediatric high-grade gliomas (pg. 352, Section “Background”, 1st paragraph). Additionally, as evidenced by Bridges, which teaches MK-1775 in the treatment of human tumor cells (Abstract), MK-1775 administration is optimally scheduled by administering the chemotherapeutic drug followed by subsequent treatment with MK-1775 (pg. 5641, Section “MK-1775 radiosensitizes human tumor cells…”, Left Col., 1st paragraph). For the above reasons, it would have been prima facie obvious for a person having ordinary skill in the art to combine the teachings of Bacha with the teachings of Bacha (2016) and Mueller, as evidenced by Bridges, to administer VAL-083 to a patient diagnosed with a different brain stem tumor, wherein that cancer is diffuse intrinsic pontine glioma, to suppress cell proliferation and further to administer a therapeutically effective quantity of a Wee1 tyrosine kinase inhibitor, wherein the Wee1 tyrosine kinase inhibitor is AZD1775. An ordinary skilled artisan would have had a reasonable expectation of success because Mueller discloses that Wee1 is significantly upregulated in pediatric gliomas (pg. 357, Section “Discussion”, Right Col., 1st paragraph). Thus, it would have been prima facie obvious for a skilled artisan, prior to the effective filing date of the instantly claimed invention, to combine the teachings of Bacha with the teachings of Bacha (2016) and Mueller as evidenced by Bridges, to arrive at the instantly claimed invention. This also reads on instant claim 10, which recites the limitation wherein the Wee1 tyrosine kinase inhibitor is AZD1775 and instant claim 12, which recites that the alkylating hexitol derivative and the Wee1 inhibitor are administered in any order.
Regarding claim 11, Bacha (2016) teaches wherein Val-083 retained cytotoxic activity in the presence of p53 mutations (Section “Conclusion”).
With respect to claim 13, while Mueller does not teach the instant combination, this reference does teach a study in which tumor-bearing mice received MK-1775 in combination with radiation therapy wherein the radiation was administered between doses of MK-1775 (pg. 354, Section “In vivo Treatment of Tumor-bearing…”, Right Col., 1st paragraph). Mueller also discloses where MK-1775 is the only Wee1 kinase inhibitor in clinical trials in combination with conventional chemotherapy (pg. 353, Section “Introduction”, Left Col., 3rd paragraph). Further, Mueller teaches wherein treatments were initiated when intracerebral tumors entered the log-phase growth as indicated by tumor bioluminescence monitoring (pg. 354, Section “In vivo Treatment of Tumor-bearing…”, Right Col., 1st paragraph). It would have been prima facie obvious to one skilled in the art to administer the combination of an alkylating hexitol derivative with the Wee1 tyrosine kinase inhibitor on the same or different days as determined through routine optimization and experimentation to determine the optimal administration schedule of both compounds for a subject in need thereof. This also reads on the limitations of instant claim 14 which recite “wherein the alkylating hexitol derivative and the inhibitor of Wee1 tyrosine kinase are administered on the same days”.
The applied reference has a common assignee and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Conclusion
No claims are allowed.
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JUSTIN CHRISTOPHER SANCHEZ
Examiner
Art Unit 1622
/J.C.S./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622