DETAILED ACTION
This office action is in response to the Applicant’s filing dated July 3rd, 2025.
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 .
Notice of Change of Examiner
Please note that the Examiner prosecuting this application has been changed to Examiner Christopher Johnson of Art Unit 1691. Please address all future correspondences to Examiner Johnson.
Status of Claims
Claims 1-3, 5 and 9-25 are pending in the instant application. Acknowledgement is made of
Applicant's remarks and amendments filed on July 3rd, 2025. Acknowledgement is made of
Applicant's amendment of claims 1, 10-11, 13-14, 16 and 19; cancelation of claims 4 and 6-8; and addition of new claims 20-25.
Priority
This application is a 371 of PCT/IL2020/051245 filed on December 3rd, 2020; and has a PRO 63/070,931 filed on August 27th, 2020 and 62/943,275 filed on December 4th, 2019.
Election/Restrictions
Applicant’s election without traverse of Group III in the reply filed on July 3rd, 2025 is acknowledged.
Claims 1-3, 5 and 9-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 3rd, 2025.
Applicant’s election without traverse of “Striatal C in Claim 17” in the reply filed on July 3rd, 2025 is acknowledged.
A prior art search was conducted for the elected species “Striatal C in claim 17”:
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Applicants state “Striatal C in claim 17” is the compound of claim 5 wherein R1 and R2 are each H.
However, the structure applicants refer to does not correspond to Striatal C in the art, CAS RN: 69075-66-7, pictured below:
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The instantly claimed “Striatal C of claim 17” derivative differs from Striatal C, CAS RN: 69075-66-7, by the dehydration and double bond formation as indicated by the red arrow and red double bond line shown below:
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For examination purposes, the instantly claimed “Striatal C of claim 17” derivative as elected by the applicants will be herein referred to by the assigned CAS RN, 2648700-88-1.
In light of the teachings of the prior art, the Examiner expanded search to Striatal C’ of instant claim 17, assigned CAS RN: 69075-66-7:
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This search retrieved prior art. Therefore, the Examiner’s search will not be extended unnecessarily to additional species in/for/during this Office Action.
This requirement is still deemed proper and is therefore made FINAL.
Claims 17-25 read on the elected species Striatal C and Striatal C’, and will be examined herein.
Claim Rejections - 35 USC § 112(a)
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 17 and 19-25 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 treating HPAF-II and PL45 human pancreatic cancer cells in vitro with “Striatal C” and Cyathus striatus CBS 126585 extract, does not reasonably provide enablement for treating all cancers in an individual. 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention and breadth of the claims
The invention relates to a method of treating an individual having cancer.
Claim 17 is directed to a method of treating an individual having cancer comprising administering to said individual a therapeutically effective amount of a striatal compound. Thus, the claim is extremely broad with regards to the diseases to be treated as well as the possible compounds that can be utilized.
2. The state and predictability of the art, and relative skill of those in the art
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
As illustrative of the state of the art, the examiner cites Gura et al., cited for evidentiary purposes, teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to justify human clinical trials. The reference further teaches that, since formal screening began in 1955, many thousands of drugs have shown activity in cell or animal models, but only 39 have actually been useful for chemotherapy (page 1041, first and second paragraphs). With regard to unpredictability, Johnson et al., also cited for evidentiary purposes, teaches that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate with activity in the same human cancer (page 1426, Results). With regard to known applications in the art, Davenport et al., also cited for evidentiary purposes, teaches that Striatal C and its analogues Striatal A and Striatal B are strong HSP-90 inhibitors (page 120, Table 10), and that HSP-90 inhibitors demonstrated anti-proliferative activity in MCF-7 human breast cancer cells (page 122, Table 11 and 3.2.1-3.2.2).
“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, 166 USPQ 18 (CCPA 1970).
Accordingly, the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statutory requirements. Furthermore, the mechanism of action of anticancer agents is often unknown or highly unpredictable, and the administration of such agents is frequently accompanied by undesirable side effects.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides data for treating HPAF-II and PL45 human pancreatic cancer cells in vitro with “Striatal C” and Cyathus striatus CBS 126585 extract (page 6, paragraph [0027]), and while structurally similar compounds can be expected to have similar effects, it is not sufficient to provide support for the full scope of treating conditions or disorders associated with all cancers.
The specification provides no particular direction or guidance for determining the particular administration regimens (e.g. timing, administration routes, etc) necessary to treat cancers encompassed by the claims, particularly in humans. At best, an "effective amount" is exemplified as a dosage sufficient to provide treatment for all cancers. While experimentation is presented for treatment of HPAF-II and PL45 human pancreatic cancer cells in vitro with “Striatal C” and Cyathus striatus CBS 126585 extract, there is no experimentation or mechanism or action presented or discussed in the specification regarding the treatment of all cancers.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that any compound of instant claim 17 could be predictably used as treatment for all conditions or disorders associated with cancer.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997). A review of the state of the art fails to reveal the mechanism of action or experimental data regarding the use of any claimed compounds or combinations to treat all known cancers. Determining if any particular claimed compound would treat a conditions or disorders associated with all known cancers would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. As noted in supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the inventions of instant claims 17 and 19-25 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Davenport et al. (High-throughput screen of natural product libraries for HSP90 inhibitors, Biology, (2014), 3(1), 101-138); in view of Gavilán et al. (Breast cancer cell line MCF7 escapes from G1/S arrest induced by proteasome inhibition through a GSK-3ß dependent mechanism. Scientific Reports, (2015), 5(10027), 1-13), cited for evidentiary purposes only.
Regarding claim 17-19, Davenport teaches Compound 111 (page 119, Figure 11) identified as Striatal C (page 120, Table 10) shown below:
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Compound 111 of Davenport is the instantly claimed compound expanded to by the examiner, Striatal C’. Davenport teaches that out of over 4000 compounds screened, 116 were identified as top performers with HSP90 inhibition values greater than 4 rSD from the median (page 101, abstract; page 107, second paragraph). Compound 111 was very potent, with an IC50 of 2µM (page 120, Table 10). Only 4 compounds had a lower IC50 value, Compound 38 (page 112, Table 3), Compound 67 and 68 (page 116, Table 7) and Compound 84 (page 119, Table 9).
Moreover, Davenport teaches a method of treating MCF-7 human breast cancer cells (addressing claim 19) with HSP90 inhibitors. Four HSP90 inhibitors were selected and further tested against MCF7 human breast cancer cells (page 101, abstract). All four HSP90 inhibitors caused a 50% reduction in growth in the 0.5–10 μM range as seen in Table 11 (page 122, 3.2.2). These results confirm the anti-proliferative properties of HSP90 inhibitors.
Gavilán, cited for evidentiary purposes only, states that the MCF-7 cell line is an ER + human epithelial (addressing claim 18) breast cancer cell line (page 10, Methods, Cells and culture conditions).
Davenport does not teach a method of treating MCF-7 human breast cancer cells with Compound 111.
It would have been prima facie obvious to a person of ordinary skill in the art to use Compound 111, a known potent HSP90 inhibitor disclosed by Davenport, to treat breast cancer; by taking advantage of the known antiproliferative activity Davenport reports in MCF-7 human breast cancer cells. In view of these teachings, selecting Compound 111 for use in the instantly claimed method would have been a predictable application of a known compound for its known property, with a reasonable expectation of success in achieving the same therapeutic effect.
Taken together, all this would result in the practice of the method of claims 17-19 with a reasonable expectation of success.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Davenport et al. (High-throughput screen of natural product libraries for HSP90 inhibitors, Biology, (2014), 3(1), 101-138), in view of Modi et al. (HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab, Clinical Cancer Research, (2011), 17(15), 5132-5139).
Regarding claim 20, Davenport teaches Compound 111, and renders the method of claims 17-19 obvious as discussed in the above rejection.
Davenport does not teach the co-administration of an anti-cancer drug with Compound 111.
Modi teaches a method of treating breast cancer wherein trastuzumab, a known anti-cancer drug, is co-administered with tanespimycin, a known HSP90 inhibitor (page 5233, Translational Relevance; page 5133, Treatment). Modi further states, “Our findings support the use of HSP90 inhibitors to overcome or delay the initiation of resistance to trastuzumab” (page 5137, right column, last paragraph).
It would have been prima facie obvious to a person of ordinary skill in the art to combine Compound 111 of Davenport, a known potent HSP90 inhibitor and demonstrated anti-proliferative activity in MCF-7 human breast cancer cells; with the known anti-cancer drug trastuzumab in the method taught by Modi, motivated by the known potent HSP90 inhibition properties of Compound 111, which would be expected to overcome the resistance to trastuzumab in breast cancer as taught by Modi. In view of these teachings, the instantly claimed method would have been a predictable application of known elements for their known properties, with a reasonable expectation of success in achieving the desired therapeutic effect.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Taken together, all this would result in the practice of the method of claim 20 with a reasonable expectation of success.
Claims 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Davenport et al. (High-throughput screen of natural product libraries for HSP90 inhibitors, Biology, (2014), 3(1), 101-138), in view of Fares et al. (EP 2576761 B1).
Regarding claims 21-24, Davenport teaches Compound 111, and renders the method of claims 17-19 obvious as discussed in the above rejection.
Davenport does not teach a Cyathus striatus CBS 126585 extract, or the co-administration of such an extract with Compound 111.
Fares teaches an extract of a medical mushroom (addressing claim 22) Cyathus striatus, known as CBS 126585 (page 3, paragraph [0016]). Fares teaches that CBS 126585 extract is useful in treating breast cancer (page 3, paragraph [0019]; page 6, paragraph [0040-0041]; page 13, claim 7). Fares states that the CBS 126585 extract is, “rich in nutraceutical agents” (addressing claim 21) (page 6, paragraph [0040]), and can be combined with extracts and biomasses of other medicinal mushrooms such as Coprinus and Tremella (addressing claim 23) (page 6, paragraph [0045]).
It would have been prima facie obvious to a person of ordinary skill in the art to combine Compound 111 of Davenport, a known potent HSP90 inhibitor and demonstrated anti-proliferative activity in MCF-7 human breast cancer cells; with the Cyathus striatus CBS 126585 extract and Coprinus and tremella medicinal mushrooms as taught by Fares, which has also been known in the art to be useful in treating breast cancer. In view of these teachings, the instantly claimed methods would have been a predictable application of known elements for their known properties, with a reasonable expectation of success in achieving the desired therapeutic effect.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Taken together, all this would result in the practice of the method of claims 21-24 with a reasonable expectation of success.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Davenport et al. (High-throughput screen of natural product libraries for HSP90 inhibitors, Biology, (2014), 3(1), 101-138), in view of Johnson et al. (Macrocyclic inhibitors of hsp90. Current Topics in Medicinal Chemistry, (2010), 10(14), 1380-1402).
Regarding claim 25, Davenport teaches Compound 111, and renders the method of claims 17-19 obvious as discussed in the above rejection.
Davenport does not teach Striatal C, CAS RN 2648700-88-1.
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Striatal C (CAS RN 2648700-88-1) differs from Striatal C’ (CAS RN: 69075-66-7) by the dehydration and double bond formation as indicated by the red arrow and red double bond line shown above. This dehydration removes a chiral center, and results in a more rigid cyclic structure.
Johnson teaches a rigid cyclic structure is optimal for HSP90 binding stating, “Data indicates that the rigid cyclic structure is critical for binding to Hsp90. Reducing the double bond between C-4 and C-5 (Fig. 5) in the backbone of the macrocycle resulted in about a 3-fold decrease in activity (IC50 = 230nM) compared to its parent GA, again suggesting that a rigid macrocycle is important for tight binding to Hsp90” (page 4, second paragraph). While Johnson illustrates this principle with the GA-derived macrocycle in Fig. 5, a person of ordinary skill in the art would have understood the disclosure as teaching a structure-activity relationship in which increased rigidity of a macrocyclic scaffold improved HSP90 binding. The dehydration of Striatal C’ to Striatal C would increase the macrocyclic scaffold’s rigidity, and predictably increase HSP90 binding affinity in line with Johnson’s teaching.
MPEP 2144.09 states:
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08 (II)(A)(4)(C).
It would have been prima facie obvious to one of ordinary skill in the art to 1) select Compound 111 of Davenport as a lead compound, motivated by the fact that this compound is exemplified as a potent HSP90 inhibitor. It would further have been prima facie obvious to 2) modify Compound 111 by dehydration, thereby creating a double bond and making the core scaffold more rigid to arrive at the originally elected compound (CAS RN 2648700-88-1) used in the instantly claimed method. The motivation to make the originally elected compound derives from the expectation that structurally similar compounds would possess similar activity (i.e., inhibit HSP90). There would have been a reasonable expectation of success in producing and using the elected compound in view of the compounds and methods taught by Davenport and modifications taught by Johnson.
Taken together, all this would result in the practice of the method of claim 25 with a reasonable expectation of success.
Conclusion
Claims 17-25 are rejected.
No claim is allowed.
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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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