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 .
Claims 4, 7, 10, 15-16, and 24-33 are cancelled.
Claims 1-3, 5-6, 8-9, 11-14, 17-23, and 34-35 are pending and under examination on the merits.
Applicant's election with traverse of Group II, claims 11-14 and 17-23 in the reply filed on 01/23/2026 is acknowledged. The traversal is on the ground(s) that Groups I-III have unity of invention because they represent the third combination of categories enumerated by 37 CFR 1,475(c). This is not found persuasive because the third combination of categories enumerated by 37 CFR 1,475(c) requires the groups to be a product, a process specially adapted for the manufacture of the product, and a use of the said product. Group I is not a process specially adapted for the manufacture of the product (the product allegedly being a disconnection agent of instant claim 35). The process to which Group I is directed is not a process for manufacture and not product is made. Instead, Group I is a screening assay process that identifies already existing compounds as having the desired properties in a specific (to the cell line used and at particular doses) context.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-3, 5-6, 8-9, and 34-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to one or more nonelected Groups/inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/23/2026.
Claims 11-14 and 17-23 are under examination on the merits.
Priority
This application is a 371 of PCT/GB2021/052449, filed 09/21/2021, which claims priority to United Kingdom 2014831.8, filed 09/21/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
IDS
The information disclosure statements (IDS’) filed 03/17/2023, 08/31/2023, and 11/13/2025 have been considered.
Notice
It appears Applicant’s claims are directed to the mechanism by which one or more prior art method(s) effect(s) treatment. The MPEP provides that:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP 2112(I) with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103,”
(see MPEP 2112(I)). Therefore, references teaching the active method steps using the same products with the same starting population will be deemed to anticipate and/or make obvious the claimed treatment method(s).
Specification
The disclosure is objected to because of the following informalities:
“cancer, best’ should read “cancer, the best” at line 17 of page 1; and
“if sufficient” should read “if a sufficient amount” at line 14 of page 3.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code (see for example, line 11 of page 10). See MPEP § 608.01.
Claim Interpretation
Applicant is advised that claims using comprising language will not be Examined as consisting of or a combination thereof (see for example, lines 15-20 of page 22 of the specification). The MPEP provides that the transitional phrases “comprising”, “consisting essentially of” and “consisting of” define the scope of a claim with respect to what unrecited additional components or steps, if any, are excluded from the scope of the claim (see MPEP §2111.03). Without a clear transitional term, the metes and bounds of the claims are indefinite and fail to provide the critical notice function to the artisan and public as to what is protected by the claim scope. Therefore, recitations of ‘comprising’ will be interpreted to comprise the following elements, but will be understood to potentially encompass more than what is explicitly recited. Recitations of ‘consisting of’ will be interpreted as closed and limited to the explicitly recited, so-modified elements.
A disconnection agent is understood to mean an agent that reduces the ability of cells to exchange, share, or transfer molecules with other cells, through connections, in particular through tumour microtubules. A disconnection agent may thus reduce the number of, inhibit the function of, or inhibit the formation of, tumour microtubules between cells. An agent which has direct toxic effects (killing more than 10% of the cells at the concentration required to have demonstrated/observed disconnection effects) would not be a "disconnection agent" in accordance with the present invention, at least for the tumour type where toxicity was observed (see for example, lines 23-33 of page 22 through lines 1-6 of page 23 of the specification).
‘About’ means +/- 10% of the modified numerical value (see for example, page 22 of the specification).
Claim Rejections - 35 USC § 112
35 USC § 112(a)
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11-14 and 17-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of disconnection agents (see for example, claim 11), encompassing the subgenus of modulators of Protein Kinase C, without disclosure of a conserved structure/representative number of species to adequately describe said genus and sub-genus. The Application discloses that PKC modulators are known in the art (see for example, lines 4-20 of page 5 of the specification) and provides a list of acknowledged modulators (see for example, lines 10-25 of page 8 and page 13 of the specification), but also discloses that the effects of a given modulator are highly dependent upon the cell/cancer/tumor type contacted with said modulator (see for example, line 19 of page 10 through line 9 of page 11 of the specification) and does not provide evidence of predictable function of a representative number of species of disconnection agent (or PKC modulators) that would function as claimed to disconnect junctions across the breadth of heterogenous cancers claimed (while killing less than 10% of the cells, see the claim interpretation section above). Therefore, in view of this disclosure, Applicant is claiming a broad genus of disconnection agents (and PCK modulators as a sub-genus) and cancers to be treated with said agents. The specification does not provide adequate written description for the entire claimed genus of disconnection agents (or PKC modulators) as claimed or cancers to be treated therewith, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which agents would be disconnection agents for treating cancer (where the agent would act as a disconnection agent) as claimed.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has disclosed 5 species of PKC modulators which function as disconnection agents, but also discloses 5 species which do not function as disconnection agents as claimed (see for example, page 27 of the specification). The five evidenced disconnection agents were only shown to function as disconnection agents in 3 solid tumor cell lines (breast cancer, glioblastoma, and hepatocellular carcinoma) in vitro (see for example, Example 2 bridging pages 26-27 of the specification; Examples 3-4 using TPPB in solid brain tumor in vivo (see for example, pages 28-31); Example 5-6 TPPB and glioblastoma in vivo (see for example, pages 31-34)).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of said disconnection agents (PKC modulators) or of the cancers to be treated therewith that confer upon said agent the ability to function as claimed because the instant specification does not provide structural/sequential features that correlate with an anti-cancer, disconnection-function as claimed. Further, the cancers for which a given agent would predictably function as claimed are not described with regard to any unifying features correlating with a reasonable probability to be treated as claimed.
Absent a clear description of the at least minimal structural features correlating with an ability to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which disconnection agents would possess the ability to function as claimed and which cancers would respond as claimed (be treated, with the disconnection agent acting as a disconnection agent) by the instantly recited method.
Furthermore, MSK (WO 1997030174 A1; citation 1 under the Foreign Patent Document section of the 03/17/2023 IDS) teaches that the agents themselves are dependent upon contact/incubation time, with regard to their effects on PKC (see for example, lines 5-25 of page 44, teaching that the effects of bryostatin-1 on PKC appear to be time and context-dependent; see further, page 70 at lines 15-20).
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which disconnection agents (PKC modulators) comprised within the genus possesses the therapeutic, disconnection function, as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of specified, evidenced, disconnection agents and specific cancers to be treated therewith having defined features, that correlate with the ability to function as claimed, and because the disclosed guidance and examples, discussed above, are not sufficient to describe the claimed genus of disconnection agents (sub-genus of PKC modulators) or the recited genus of cancers, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of disconnection agents that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some compounds/agents and cancers that fall within the scope of the claim. Of course, depending on what agents/cancers are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face. The claims not only encompass agents which are not yet known to have this function, but also encompass agents/compounds which have not yet been invented.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
Therefore, claims 11-14 and 17-23 are deemed to fail to meet the written description requirement, as presently drafted. The disclosure fails to provide written description for the claimed genus of disconnection agents. The genus of disconnection agents is not limited to a particular class (protein, antibody, aptamer, etc). The genus of disconnection agents, as recited, is not described by a representative number of species of a structure-function correlation. The genus of disconnection agents encompasses the subgenus of PKC modulators. The subgenus of PKC modulators is also not described by a representative number of species of a structure-function correlation in the instant disclosure. Therefore, both the genus of disconnection agents and the encompassed subgenus of PKC modulators are undescribed and fail to meet the written description requirement of 35 USC §112(a).
Enablement
Claims 11-14 and 17-23 are 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 treatment of brain cancer (including glioblastoma), breast cancer, pancreatic cancer, lung cancer, liver cancer (hepatoma), stomach cancer (gastric cancer), ovarian cancer, and neuroblastoma, does not reasonably provide enablement for treatment of other cancers. 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.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claims 11-14 and 17-23 are broadly directed to a method for treating cancer comprising administering a disconnection agent before or concomitant with administration of a toxic agent. This encompasses a broad range of potential cancers.
The nature of the invention
Claims 11-14 and 17-23 are broadly directed to a method for treating cancer. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that extrapolation of in vitro results to in vivo treatment, as well as cancer treatment in general, is unpredictable and that cancer is a highly heterogenous disease with no universal cure (see the discussion of unpredictability in the prior art, below, at subsection (E) of this rejection).
The level of one of ordinary skill
As the claims are directed to a method for treatment of cancer, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
In the instant case, those of skill in the art recognize that the treatment of cancer, in
general is at most unpredictable, as underscored by Gura (Science, 1997, 278(5340)) who discusses the potential shortcomings of potential anti-cancer agents including extrapolating from in vitro to in vivo protocols, the problems of drug testing in knockout mice, and problems associated with clonogenic assays. Indeed, from the time formal screening began in 1955 to the date of the reference, thousands of drugs have shown activity in either cell or animal models, but only 39 that were used exclusively for chemotherapy, as opposed to supportive care, had won approval from the FDA (page 1041, 1st column) wherein the fundamental problem in drug discovery for cancer is that the model systems are not predictive. Moreover, those of skill in the art recognize that in vitro assays are generally useful to observe basic phenomenon such as preliminary screening of potential drugs. However, clinical correlations are generally lacking. The greatly increased complexity of the in vivo environment as compared to the very narrowly defined and controlled conditions of an in vitro assay does not permit a single extrapolation of in vitro assays to human therapeutic efficacy with any reasonable degree of predictability. In vitro assays cannot easily assess cell-cell interactions that may be important in a particular pathological state. Furthermore it is well known in the art that cultured cells, over a period time, lose phenotypic characteristics associated with their normal counterpart cell type. Freshney (Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York, p4) teach that it is recognized in the art that there are many differences between cultured cells and their counterparts in vivo. These differences stem from the dissociation of cells from a three-dimensional geometry and their propagation on a two-dimensional substrate. Specific cell interactions characteristic of histology of the tissue are lost. The culture environment lacks the input of the nervous and endocrine systems involved in homeostatic regulation in vivo. Without this control, cellular metabolism may be more constant in vitro but may not be truly representative of the tissue from which the cells were derived. This has often led to tissue culture being regarded in a rather skeptical light (p. 4, see Major Differences In Vitro). Further, Dermer (Bio/Technology, 1994, 12:320) teaches that, "petri dish cancer" is a poor representation of malignancy, with characteristics profoundly different from the human disease. In addition, Dermer teaches that when a normal or malignant body cell adapts to immortal life in culture, it takes an evolutionary type step that enables the new line to thrive in its artificial environment. This step transforms a cell from one that is stable and differentiated to one that is not. Yet normal or malignant cells in vivo are not like that. The reference states that evidence of the contradictions between life on the bottom of a lab dish and in the body has been in the scientific literature for more than 30 years. Zips et al. (2005, In Vivo 19:1-8) indicate that while in vitro assays are useful as a first step, a cancer therapeutic must be evaluated in vivo for therapeutic benefit (abstract, top of p. 3, p. 6 conclusion). An editorial in Nature Biotechnology in 2013 reviews similar studies and arrives at the same conclusions (2013, Nature Biotechnology 31:85).
Clearly it is well known in the art that cells in culture exhibit characteristics different
from those in vivo and cannot duplicate the complex conditions of the in vivo environment involved in host-tumor and cell-cell interactions. Moreover, as taught by The Marshal Protocol (Differences between in vitro, in vivo, and in silico studies, obtained from: https://mpkb.org/home/patients/assessing_literature/in_vitro_studies (2024)), one weakness of in vitro studies is that they fail to replicate the precise cellular conditions of an organism…because of this, in vitro studies may lead to results that do not correspond to the circumstances occurring around a living organism….[further] in vitro studies fails to account for in vivo concentrations of molecules (such as for competition for nuclear receptors). Finally, the art teaches the heterogeneity of cancers and lack of a universal cure (see Allison et al (Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014) at exemplary paragraph 1 of the Introduction) and American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be cured.html)(2021)). Clearly it is well known in the art that cells in culture exhibit characteristics different from those in vivo and cannot duplicate the complex conditions of the in vivo environment involved in complex/systemic disease/pathology.
(F) The amount of direction provided by the inventor
Applicant discloses 6 working examples of 5 agents (see the discussion of working examples, below at subsection (F) of this rejection).
The existence of working examples
Applicant has disclosed 5 species of PKC modulators which function as disconnection agents, but also discloses 5 species which do not function as disconnection agents as claimed (see for example, page 27 of the specification). The five evidenced disconnection agents were only shown to function as disconnection agents in 3 solid tumor cell lines in vitro (breast cancer, glioblastoma, and hepatocellular carcinoma) (see for example, Example 2 bridging pages 26-27 of the specification) and in brain cancer in vivo (see for example, Examples 3-4 using TPPB in solid brain tumor in vivo at pages 28-31 of the specification; see also for example, Example 5-6 TPPB and glioblastoma in vivo at pages 31-34 of the specification).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. Only 5 agents are shown to function as disconnection agents in 3 cancer types in vitro and said agents are only shown to treat brain cancer (glioblastoma) in vivo. The artisan would be forced into burdensome experimentation so as to determine which agents function as disconnection agents (and in what dosing/concentration, contact time, and for which cancers (killing less than 10% of cells, for example) and for which cancers said disconnection effect is therapeutic.
Thus, claims 11-14 and 17-23 are deemed to lack enablement for the full scope of embodiments claimed. Only for treatment of brain cancer (including glioblastoma), breast cancer, pancreatic cancer, lung cancer, liver cancer (hepatoma), stomach cancer (gastric cancer), ovarian cancer, and neuroblastoma is deemed enabled at present.
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.
(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.
Claim(s) 11-14, 17, and 20-22 is/are rejected under 35 U.S.C. 102(a)(1 and 2) as being anticipated by MSK (WO 1997030174 A1; citation 1 under the Foreign Patent Document section of the 03/17/2023 IDS).
Regarding claim 11, MSK teaches that Protein kinase C (PKC) functions in processes relevant to carcinogenesis, tumor cell metastasis, and apoptosis. Safingol, an optical isomer (the L- threo enantiomer) of dihydrosphingosine, is a specific inhibitor of PKC and may represent a novel target for anti-cancer therapy. Preclinical animal studies show that safingol alone has minimal effects on tumor cell growth and is non-toxic at doses that achieve serum levels sufficient to inhibit PKC enzyme activity, but combination of this compound with conventional chemotherapy agents, such as doxorubicin and cisplatin, dramatically potentiates their anti-tumor effects. It has been suggested that many chemotherapeutic agents exert their anti-tumor effects by inducing apoptosis (see for example, pages 1-3). The invention of MSK provides a modulating agent (such as the taught the PKC inhibitor(s)) which increase apoptosis in tumor cells when combined with an antitumor agent (see for example, pages 12-13). Administration of the PKC-modulating agent/apoptosis modulating agent may be prior to or concomitant with administration of the therapeutic agent (see for example, claims 15 and 35 at pages 305 and 208, respectively). Administration and proof of concept are shown, for example, in human gastric cancer cells and murine mammary carcinoma (see for example, page 194 and pages 195-197; reading on treatment of a subject that is a mammal).
Because MSK teaches a method of treating a mammal with a tumor (presumed to be ‘in need of such treatment’ in the noted absence of a different or preclusive definition of said instant preamble recitation) comprising administering a disconnection agent (such as a PKC inhibitor such as Safingol (noted as only 1 of the taught modulatory agents; which notably, on its own, is not cytotoxic) prior to or concomitant with administration of a toxic agent (such as doxorubicin or cisplatin; notably only 2 of the many taught toxic agents) toxic to cells of the tumor, MSK is deemed to anticipate instant claim 11.
Regarding claim 12, as noted above, Safingol is a specific inhibitor of PKC, anticipating instant claim 12.
Regarding claims 13-14, MSK teaches that the invention is a method of enhancing therapy in a tumor bearing subject comprising administering to the subject an effective amount of a specific protein kinase C modulator/inhibitor capable of potentiating apoptosis in tumor cells during or prior to the treatment of an antitumor therapeutic agent, wherein the specific protein kinase C modulator may be bryostatin 1 (macrocyclic lactone) (see for example, the paragraph bridging pages 18-19, pages 34-35, 40, 44, and claims 15 and 27 at pages 205-206 (noting that MSK further teaches that byostatin-1 is an activator of PKC (see lines 5-25 of page 44, teaching that the effects of bryostatin-1 on PKC appear to be time and context-dependent; see further, page 70 at lines 15-20 of MSK))). Because the same compound must have the same effects when administered the same way to the same population, the teachings of MSK anticipate instant claims 13 and 14, noting that there is no recited active step that would distinguish the method of MSK from the claimed method, as presently drafted.
Regarding claim 17, MSK teaches that the method may be practiced in the context of treating breast cancer, pancreatic cancer, lung cancer, liver cancer (hepatoma), stomach cancer (gastric cancer), or ovarian cancer (see for example, lines 10-25 of page 6 and claims 15 and 32-34 at pages 205 and 207). Therefore, MSK anticipates instant claim 17.
Regarding claim 20, MSK teaches treatment pf human gastric cancer cells with safingol for only 1 hour prior to 24 hours of treatment with MMC (a chemotherapeutic drug) resulted in an increase in apoptosis (44%±4% of exposed cells) that was essentially equivalent to that which was observed with concomitant exposure of the cells to the two drugs for the entire 24 hour interval (see for example, pages 3, 21, and 23-24; noting that MSK additionally teaches administration of PKC modulator (such as safingol) 30 minutes, 1 hr, 3hrs, 6hrs, 18hrs, and 24hrs prior to exposure with an toxic agent (such as the chemotherapeutic agent MMC) at exemplary page 96). MSK therefore anticipates instant claim 21.
Regarding claim 21, MSK teaches a method for treating cancer in a subject comprising administering to the subject an effective amount of at least one antitumor therapeutic agent, and at least one modulating agent, sequentially (wherein the tumor bearing subject is administered at least one PKC-modulating agent and subsequently administered at least one antitumor therapeutic agent) or concomitantly, wherein at least one of the antitumor therapeutic agents is a radiotherapeutic agent (understood to encompass/read upon radiation therapy by art-known means; this appears to be consistent with the instant claim scope in light of lines 5-20 of page 23 of the instant specification which appears to equate a radiotherapeutic agent with radiation) (see for example, claims 15, 19, and 31 at pages 205 and 207). Therefore, MSK anticipates instant claim 21.
Regarding claim 22, MSK teaches a method for treating cancer in a subject comprising administering to the subject an effective amount of at least one antitumor therapeutic agent, and at least one modulating agent, sequentially (wherein the tumor bearing subject is administered at least one PKC-modulating agent and subsequently administered at least one antitumor therapeutic agent) or concomitantly, wherein at least one of the antitumor therapeutic agents is a chemotherapeutic agent (see for example, claims 15, 19, and 30 at pages 205 and 207).
Therefore, MSK anticipates instant claim 22.
Claim(s) 18 is/are rejected under 35 U.S.C. 102(a)(1 and 2) as being anticipated by MSK (WO 1997030174 A1), as applied to claims 11-14, 17, and 20-22 above, as evidenced by Serwer et al (J Vis Exp. 2010 Aug 16;(42):1992. doi: 10.3791/1992).
Regarding claim 18, MSK anticipates the method of instant claim 11 and further teaches intravenous and/or intraperitoneal administration of safingol (see for example, pages 55-57 and 61), infusion of UCN-01 (see for example, pages 61 and 63 (also teachings that administration (route and dosing) would be selected based upon prior art teachings)), intravenous and/or intraperitoneal administration of a 20-mer that inhibits PKCα (see for example, page 75), and intravenous administration of flavopiridol (see for example, pages 126 and 165) (where safingol, UCN-01, the 20-mer that inhibits PKCα, and flavopiridol are taught to be PKC inhibitors and other PKC modulators, including bryostatin-1, are taught to be ripe for clinical trials where doing and route would depend upon the prior art safety and efficacy data (see for example, page 63)). Intravenous, infusion, and intraperitoneal administration are widely known in the art to be means for systemic administration (as evidenced by Serwer et al at exemplary page 1 of 6).
Therefore, MSK as evidence by Serwer et al, anticipates the method of instant claim 18.
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.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over MSK (WO 1997030174 A1; citation 1 under the Foreign Patent Document section of the 03/17/2023 IDS), as applied to claims 11-14, 17, and 20-22 above, in view of Jonathan et al (Blood 2015; 126 (23): 1552. doi: https://doi.org/10.1182/blood.V126.23.1552.1552).
Regarding claim 19, MSK anticipates instant claim 11 (noting that the cancers MSK teaches that the method may be practiced in are breast cancer, pancreatic cancer, lung cancer, liver cancer (hepatoma), stomach cancer (gastric cancer), or ovarian cancer (see for example, lines 10-25 of page 6 and claims 15 and 32-34 at pages 205 and 207)), as discussed above.
MSK does not teach administration local to the tumor.
However, Jonathan et al teach that intratumoral (held to read on the recitation of administration local to the tumor) administration of immunotherapeutic agents has several advantages including 1) higher concentrations of agents in close proximity to target antigens and tumor-infiltrating lymphocytes 2) lower doses overall with less systemic exposure and toxicity 3) potentially a novel mechanism of action such as depletion of intratumoral Tregs 4) potential for an abscopal effect, essentially acting as an in-situ cancer vaccine (see for example, paragraph 1 of the abstract at page 1).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to use the invention as claimed to achieve the noted anti-cancer effects taught by MSK while, at least reducing any potential off-target effects and/or toxicities and potentially recognizing one or more of the additionally enumerated benefits associated with intratumoral administration.
The MPEP provides that:
“The Supreme Court in KSR reaffirmed the familiar framework for determining obviousness as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), but stated that the Federal Circuit had erred by applying the teaching-suggestion-motivation (TSM) test in an overly rigid and formalistic way. KSR, 550 U.S. at 404, 82 USPQ2d at 1391. Specifically, the Supreme Court stated that the Federal Circuit had erred in four ways: (1) “by holding that courts and patent examiners should look only to the problem the patentee was trying to solve ” (Id. at 420, 82 USPQ2d at 1397); (2) by assuming “that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem” (Id.); (3) by concluding “that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try’” (Id. at 421, USPQ2d at 1397); and (4) by overemphasizing “the risk of courts and patent examiners falling prey to hindsight bias” and as a result applying “[r]igid preventative rules that deny factfinders recourse to common sense” (Id.). See also Novartis Pharms. Corp. v. West-Ward Pharms. Int'l Ltd., 923 F.3d 1051, 1059, 2019 USPQ2d 171676 (Fed. Cir. 2019); Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1047-48, 120 USPQ2d 1400, 1410 (Fed. Cir. 2016); and Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1332, 102 USPQ2d 1445, 1449 (Fed. Cir. 2012)… Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Id. (2) “In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation.” Id. at 416-17, 82 USPQ2d at 1395. (3) “[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious. The Supreme Court further stated that:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. Id. at 417, 82 USPQ2d at 1396.
When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id,”
(see MPEP §2141(I)). It would have been obvious for the artisan to try locally administering the disconnection agent (PKC modulator), such as the modulators of MSK, by known means such as by intertumoral administration as taught by Jonathan et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over MSK (WO 1997030174 A1; citation 1 under the Foreign Patent Document section of the 03/17/2023 IDS), as applied to claims 11-14, 17, and 20-22 above, in view of Hardman et al (Nat Commun 11, 1879 (2020). https://doi.org/10.1038/s41467-020-15742-7).
Regarding claim 23, MSK teaches the use of different, individual PKC modulators for treating breast cancer, pancreatic cancer, lung cancer, liver cancer (hepatoma), stomach cancer (gastric cancer), or ovarian cancer administered before or concomitant with a treatment/toxic agent (see for example, claims 15, 19, and 32-35 at pages 205-208, lines 10-25 of page 6).
MSK does not teach that the treatment/toxic agent is an immunotherapy.
However, Hardman et al teach that targeted biologics and cell therapies for the treatment of cancer, including monoclonal antibodies (mAbs), antibody-drug conjugates (ADC’s), bi- and tri-specific antibodies (biAbs, triAbs), chimeric antigen receptor (CAR) T and NK cell therapies, and neoantigen-directed cell therapies, are revolutionizing oncology. By targeting tumor-specific cell surface antigens and neoantigens, these therapies offer distinct advantages over traditional treatment options as they avoid the systemic toxicity associated with cytotoxic chemotherapies while efficiently and selectively clearing malignant cells. However, durability of patient-response to said treatments is observed to diminish across a variety of settings due top variable and decreased antigen density. Protein kinase C (PKC) modulators offer a potentially general solution to this antigen density and persistence problem. Among the most studied PKC modulators, plant-derived phorbol esters (PEs) have long been known to influence antigen expression in a variety of cell lines. Additionally, bryostatin 1, a marine macrolide and potent PKC modulator, also alters expression of surface antigens in tumor cell lines, making them more immunogenic and thus more susceptible to immune or other antigen-targeted clearance strategies. Indeed, several pre-clinical and clinical studies have reported that bryostatin 1 (where bryostatin-1 and its synthesized analogues are understood to activate PKC, see for example, the results section at pages 3-8) can alter the immunophenotype and increase the immunogenicity of cancer cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma (NHL). These and related studies indicate that PKC modulators can enhance expression and persistence of certain antigens, potentially enhancing a variety of (neo)antigen-targeted therapies (see for example, column 1 of page 2). Hardman et al designed and prepared a set of structurally diverse analogs and evaluated how variations in their structures influence their binding to PKC, their in vitro translocation of a PKC fusion protein, and their enhancement of CD22 antigen density in in vitro models of ALL and AIDS-related NHL (see for example, column 2 of page 8). Hardman et al teach that these synthetic studies have enabled access to a class of promising leads for enhancing antigen-targeted immunotherapy, including enhanced CD22-targeted CAR T therapy (see for example, column 1 of page 9).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to use the invention as claimed to enhance antigen-targeted immunotherapy, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 13 is/are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Phipps et al (US 20050020482 A1) in view of Baskar et al (Int J Med Sci. 2012;9(3):193-9. doi: 10.7150/ijms.3635).
Phipps et al teach a method of treating a cancer/tumour (noting that Phipps limits its discussion and teachings to treatment of neuroblastoma and certain breast cancers (see the disclosure generally with paragraphs 0012 (column 1, page 2), 0035 (column 1, page 3), 0039 (column 3, page 3), column 0047 (column 1, page 4), and tables 1-3 and claim 11 (pages 6-7)) where the teachings of Phipps are being understood as limited to neuroblastoma and breast cancer) in a patient, comprising the steps of: (a) providing the cell with a protein kinase A (PKA) activator; and (b) providing the cell with modulator for specifically inhibiting or activating one or more PKC isoforms (see for example, claim 17).
Phipps et al do not teach additionally, subsequent of concomitant treatment with a toxic agent (understood to comprise, for example, a chemotherapeutic agent or radiotherapy).
However, Baskar et al teach that cancer treatment modalities include radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy (see for example, the abstract at page 193).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to use the invention as claimed to achieve treat cancer because the MPEP provides that it is obvious to combine known elements where there is motivation in the art (see MPEP section 2143(I)(G)) or where the combination according to known methods yields predictable results (see MPEP section 2143(I)(A)). Here, the combination of elements known to treat cancer would be predictably combined to achieve the same purpose of treating cancer. Further the art provides motivation to combine because Baskar et al teach that, with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century, but that radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer, which would motivate the artisan to combine a known therapy, such as radiation therapy, with the method of Phipps et al to enhance cancer treatment results. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 20180221479 A1 (disclosing an agent for use in the treatment of glioma in a subject, wherein said agent is capable of interfering with tumor microtube (TM)-mediated (a) invasion and/or (b) proliferation and/or (c) intracellular communication and/or (d) resistance to radiotherapy and/or chemotherapy of glioma cells);
Roehlecke et al ( Cancers. 2020; 12(4):857. https://doi.org/10.3390/cancers12040857);
Morley et al (Cell Tissue Res 340, 229–242 (2010). https://doi.org/10.1007/s00441-010-0938-z);
Potthoff et al (Cancers 2019, 11, 858; Cancers 2019, 11, 858);
Nihei et al (BMC Cell Biology 2010, 11:3);
Kreitzburg et al (Cancer Drug Resist 2018;1:181-97; http://dx.doi.org/10.20517/cdr.2018.06)
Newton et al (Trends in Pharmacological Sciences, May 2017, Vol. 38, No. 5; http://dx.doi.org/10.1016/j.tips.2017.02.002)
McIlwain et al (xPharm: The Comprehensive Pharmacology Reference, Elsevier, 2008,
Pages 1-5, ISBN 9780080552323, https://doi.org/10.1016/B978-008055232-3.63983-2);
Kraft et al (Cancer Res. 1992 Apr 15;52(8):2143-7. PMID: 1559218.);
Dickson et al (Clin Cancer Res. 2011 April 15; 17(8): 2484–2492. doi:10.1158/1078-
0432.CCR-10-2323; a phase I clinical trial of safingol in combination with cisplatin in
advanced solid tumors);
Haimovitz-Friedman et al (Cancer Research 54, 2591-2597, May 15, 1994;
disclosing that PKC mediates protection of cells against radiation-induced apoptosis);
The sources cited on the 11/13/2025 IDS;
The sources cited on the 03/17/2023 IDS; and
The sources cited on the 08/31/2023 IDS
are deemed relevant to claimed subject matter.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent
Application Information Retrieval (PAIR) system. Status information for published applications
may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
applications is available through Private PAIR only. For more information about the PAIR
system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would
like assistance from a USPTO Customer Service Representative or access to the automated
information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights