DETAILED ACTION
This office action is in response to the Applicant’s filing dated November 13th, 2023.
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 .
Status of Claims
Claims 1-17 and 20 are pending in the instant application. Acknowledgement is made of
Applicant's remarks and amendments filed on November 13th, 2023. Acknowledgement is made of
Applicant's amendment of claims 6-17 and 20; and cancelation of claims 18-19 and 21-117.
Priority
This application has a PRO of 63/388,479 filed on July 12th, 2022.
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 1-17 and 20 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 SJSA1 tumors with Navtemadlin, does not reasonably provide enablement for treating all tumors, particularly in humans, with any of the claimed MDM2 inhibitors. 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 a subject having tumors.
Claims 1-17 and 20 are directed to a method of treating a subject, particularly a human as recited in claim 16, having a tumor using an MDM2 inhibitor. Thus, the claims are 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). Wang et al., cited for evidentiary purposes, states “Acquired or intrinsic resistance to molecularly targeted therapies or chemotherapy has always been a major problem in the development of anticancer drugs. Long-time treatment with MDM2 inhibitors generally leads to acquired resistance. MDM2 inhibitors can not only activate p53 in cancer cells, but also activate p53 in normal cells and tissues, which might lead to unwanted side effects, such as spleen, bone marrow, and small intestines. Both RG7112 and Idasanutlin have been reported to cause thrombocytopenia, a major dose limiting toxicity” (page 17, last paragraph).
“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 in Example 2 on pages 48-49, showing significant tumor growth inhibition in SJSA1 tumors when treated with Navtemadlin, but is not sufficient to provide support for the full scope of compounds encompassed by the claims or for the full scope of conditions or disorders associated with all tumors.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed in supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that any MDM2 inhibitor could be predictably used as treatment for all conditions or disorders associated with all tumors.
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 data to enable the claims of using MDM2 inhibitors to treat all tumors. Determining if any particular claimed method would treat a conditions or disorders associated with all tumors with any MDM2 inhibitor would require synthesis of the compounds, 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 1-17 and 20 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 1-17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (US 2022/0175725 A1).
Regarding claims 1-10 and 13-17 and 20, Yang teaches Example 3 (page 36) wherein APG-115 (page 10, paragraph [0124]) shown below is administered orally in dosing regimens of either 10mg/kg or 50mg/kg every other day to subjects with colon tumors. Treated vs Control (T/C), expressed in a percentage value, showed efficacy across all regimens (page 36, Table 11):
PNG
media_image1.png
450
737
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Greyscale
Yang also teaches Example 7 (pages 38-40) wherein APG-115 is administered orally to human patients who had various cancers comprising breast cancer, lung cancer, ovarian cancer and pancreatic cancer (page 39, Table 12) Yang discloses that it is alternatively useful to administer compositions comprising APG-115 by injecting directly into a tumor (page 5, right column, paragraph [0065]). APG-115 is an MDM2 inhibitor (page 10, paragraph [0124]) and the seventh compound listed of instant claim 20. Yang further teaches various dosage regimens for APG-115 ranging from 5mg/kg/week to 700mg/kg/week (page 22, paragraph [0198]).
Yang does not explicitly disclose a treatment regimen wherein the dose is delivered at most once every 3 days, or the therapeutically effective amounts for that regimen.
It would have been prima facie obvious to a person of ordinary skill in the art to utilize the amounts of APG-115 taught by Yang as a starting point for optimizing the amount and treatment regimen of APG-115 utilized to treat cancer administered by direct injection into a tumor, since Yang teaches APG-115 is useful for treating cancer, and it is alternatively useful to administer by injecting directly into a tumor; and because dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 (II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claims 12-13, The prior art is silent regarding "reducing the tumor volume by at least 20-50%". However: “reducing the tumor volume by at least 20-50%" will naturally flow from the method made obvious by the prior art (see above rejection), since the same compound (APG-115) is being administered to the same subjects (patients having a tumor). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
In other words, even though the prior art is silent regarding "reducing the tumor volume by at least 20-50%", by practicing the method made obvious by Yang, one will also be "reducing the tumor volume by at least 20-50%", even though the prior art was not aware of it.
Apparently, Applicant has discovered a new property or advantage ("reducing the tumor volume by at least 20-50%") of the method made obvious by Yang.
MPEP 2145 (II) states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Taken together, all this would result in the method of instant claims 1-17 and 20 with a reasonable expectation of success.
Conclusion
Claims 1-17 and 20 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