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 .
Non-Final Rejection
The Status of Claims:
Claims 1, 19, 21, 39, 46-56 are pending.
Claims 21 and 46-56 are rejected.
Claims 1, 19, 39, 54 are objected.
Claims 1, 19 and 39 are withdrawn from consideration.
DETAILED ACTION
1. Claims 21 and 46-56 are under consideration in this Office Action.
Priority
2. It is noted that this application is a 371 of PCT/CN2022/109762 08/02/2022 , which has a foreign application, PCT/CN2021/110099 08/02/2021.
Drawings
3. The drawings filed on 2/01/2024 were accepted by the examiner.
IDS
4. The IDS filed on 3/11/2025 & 2/01/2024 are reviewed by the examiner.
Election/Restriction
Applicant’s election without traverse of Group III ( Claims 41 and 44 ) which was canceled and currently revised Claim 21 and new 46-56 on 5/22/26 is acknowledged.
Claims 1, 19 and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups I-II, there being no allowable generic or linking claim.
The elected species are in the followings:
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; the only elected species of the IAP inhibitors is allowable, while the other species of Bcl-2 inhibitor, and MDM2 are not allowable.
Claim Objections
Claims 1, 19, 39, 54 are objected to because of the following informalities:
In claims 1, 39, the expression “ (Currently Amendment) is recited ,whereas in claim 19 , the expression “(Previously Presented) “ is recited.
These expressions are improper. Their expressions should be changed to “(Currently Withdrawn)”. An appropriate correction is required.
In claim 54, the expression “ ; or ” is recited without the period at the end of the claim. This expression is improper.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 21,46-56 are rejected 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the incorporation of essential material in the specification by reference to a foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference which have to be non-essentials to the claimed invention. The amendment must be accompanied by an affidavit or declaration executed by the applicant, or a practitioner representing the applicant, stating that the amendatory material consists of the same material incorporated by reference in the referencing application. See In re Hawkins, 486 F.2d 569, 179 USPQ 157 (CCPA 1973); In re Hawkins, 486 F.2d 579, 179 USPQ 163 (CCPA 1973); and In re Hawkins, 486 F.2d 577, 179 USPQ 167 (CCPA 1973).
The attempt to incorporate subject matter regarding the synthesis of compounds (A-E) into this application by references to WO 2018/027097A1. line 10 ; WO2015/161032A1, line 12; WO 2014/031487A1, line 14; WO 2014/113413A1, line 17
on page 36, is improper because the specification mentions that “ the disclosure of the above reference documents are incorporated herein by reference”, which has been incorporated into the specification. They are foreign patent; they do specify essential materials which are reflected in the instant claims. Applicant is required to amend the disclosure to include the material incorporated by references and to accompany the amendment by an affidavit or declaration by the applicant.
Claims 21, 46-56 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making salts of the claimed compounds, does not reasonably provide enablement for making solvates of the claimed compounds. The specification does not enable any person skilled in the art of synthetic organic chemistry to make the invention commensurate in scope with these claims. “The factors to be considered [in making an enablement rejection] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. In the present case the important factors leading to a conclusion of undue experimentation are the absence of any working example of a formed solvate, the lack of predictability in the art, and the broad scope of the claims.
c) There is no working example of any hydrate or solvate formed. The claims are drawn to solvates, yet the numerous examples presented all failed to produce a solvate. These cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However ... there is no evidence that such compounds exist... the examples of the '881 patent do not produce the postulated compounds... there is ... no evidence that such compounds even exist.” The same circumstance appears to be true here. There is no evidence that solvates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that solvates can be made, or limit the claims accordingly.
g) The state of the art is that is not predictable whether solvates will form or what their composition will be. In the language of the physical chemist, a solvate of organic molecule is an interstitial solid solution. This phrase is defined in the second paragraph on page 358 of West (Solid State Chemistry). West, Anthony R., "Solid State Chemistry and its Applications, Wiley, New York, 1988, pages 358 & 365. The solvent molecule is a species introduced into the crystal and no part of the organic host molecule is left out or replaced. In the first paragraph on page 365, West (Solid State Chemistry) says, “it is not usually possible to predict whether solid solutions will form, or if they do form what is their compositional extent". Thus, in the absence of experimentation one cannot predict if a particular solvent will solvate any particular crystal. One cannot predict the stoichiometery of the formed solvate, i.e. if one, two, or a half a molecule of solvent added per molecule of host. In the same paragraph on page 365 West (Solid State Chemistry) explains that it is possible to make meta-stable non-equilibrium solvates, further clouding what Applicants mean by the word solvate. Compared with polymorphs, there is an additional degree of freedom to solvates, which means a different solvent or even the moisture of the air that might change the stabile region of the solvate.
h) The breadth of the claims includes all of the hundreds of thousands of compounds of formulas V, VI, I , compounds A-E as well as the presently unknown list of solvents embraced by the term "solvate". Thus, the scope is broad.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Thus, undue experimentation will be required to practice Applicants' invention.
Claims 21, 46-56 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating specific diseases, does not reasonably provide enablement for lowering its (cancer) risk. 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. Applicants are not enabled for preventing any of these diseases or lowering its (cancer) risk. The only established prophylactics are vaccines not the claimed drug such as present here. In addition, it is presumed that “prevention” or “ lowering its risk” of the claimed cancer diseases would require a method of identifying those individuals who will develop the claimed cancer diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted.
“The factors to be considered [in making an enablement rejection] have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art, and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. 1) As discussed above, preventing or lowering its risk of the cancer requires identifying those patients who will acquire the disease before cancer occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 3) The claims rejected are drawn to clinical preventative medicine and are therefore physiological in nature. 4) The state of the art is that no general procedure is art-recognized for determining which patients generally will become the patients with a disease or disorder or condition response to an immune system before the fact. 6) The artisan using Applicants invention would be a Board Certified physician in the cancer disease or condition response to the immune system with an MD degree and several years of experience. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for lowering a risk for a cancer disease or disorder or condition response to an immune system generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent psoriasis generally. That is, the skill is so low that no compound effective generally against the disease or disorder or condition response to an immune system has ever been found let alone one that can prevent such conditions. 7) It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases.
The Examiner suggests deletion of the word “ lowering its risk (cancer )” from the claims.
Claims 21,46-56 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 acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or multiple myeloma (MM), does not reasonably provide enablement for any other various cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, unrelated to the invention commensurate in scope with these claims.
Different types of cancer cells affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. Thus, it is beyond the skill of oncologists today to get an agent to be effective against various cancer cells, evidence that the level of skill in this art is low relative to the difficulty of such a task.
In evaluating the enablement in question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed.
The Nature of the Invention
The nature of the invention in claim 21 is as followed:
A method for treating or suppressing a cancer, reducing its severity, lowering its risk or inhibiting its metastasis in an individual, comprising administering to the individual: a therapeutically effective amount of the pharmaceutical combination of claim--(i) a pharmaceutical combination comprising and one or more anticancer reagents comprising a MDM2 inhibitor, an IAP inhibitor, or a combination thereof; (ii) a pharmaceutical combination comprising a MDM2 inhibitor and one or more anticancer reagents comprising a Bcl-2 inhibitor, an IAP inhibitor, or a combination thereof: or (iii) a pharmaceutical combination comprising a Bcl-2/Bcl-xL inhibitor and one or more anticancer reagents comprising a MDM2 inhibitor, an IAP inhibitor, or a combination thereof.
The predictability or lack thereof in the art
The instant claimed invention is highly unpredictable as discussed below:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the modifications of formulas V, VI, and I with various substitutes in the specification could result in a significant difference in their properties and activity for treating various cancers.
Hence, in the absence of a showing of correlation between all the well-known cancers encompassed by the instant claims and the effectiveness of all the combination of a Bcl-2 inhibitor, a MDM2 inhibitor, an IAP inhibitor and /or a Bcl-2/Bcl-xL inhibitor for treating any cancer cells, one of skill in the art is unable to fully predict possible results from the administration of the compounds of formulas V, VI, and I with various substitutes.
The nature of pharmaceutical arts is that it involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities. There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The presence or absence of working examples
There are examples (2-17) for testing and potentially treating a purpose of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or multiple myeloma (MM) by using a sigle or combined compounds of A, B, C, D and/or E.
But there are no other actual working examples for performing the assays using other types of cancer cells in the specification. Thus, the specification fails to provide sufficient working examples as to how all the heterogeneities of various kinds of cancers can be treated or suppressed or inhibiting their metastasis in any individual successfully by the use of the compounds.
The breadth of the claims
The breadth of the claims is that all the combination of a Bcl-2 inhibitor ,a MDM2 inhibitor, an IAP inhibitor and /or a Bcl-2/Bcl-xL inhibitor can treat or suppress or inhibit their metastasis any cancers , without regards as to the clinical the side effects of using the compounds on various types of the cancers.
The level of the skill in the art
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine which compounds exhibit the desired pharmacological activity for treating or suppressing or inhibiting their metastasis
in all the heterogeneities of the cancer cells.
Thus, the specification fails to provide sufficient support of the compounds for treatment or inhibition of their metastasis in all the heterogeneities of the claimed cancers. As a result, it necessitates one of the skilled artisans in the art to perform an exhaustive search for selecting claimed cancers suitable for the compounds in order to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001 (3/13/1997), states that “ a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent 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”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test whether or not all the claimed cancers can be treated, suppressed or inhibited by the compounds, which is encompassed in the instant claims, with no assurance of success.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 21, 46-47, 49-51, and 54-55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated clearly by Yang et al (WO 2020/024820 A1).
Yang et al discloses a method of treating a cancer by using a combination product comprising a Bcl-2 inhibitor and an MDM-2 inhibitor in the followings:
6. The combination according to any one of claims claim 1 to 4, wherein the Bcl-2 inhibitor is the following compound or a pharmaceutically acceptable
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salt and wherein the MDM2 inhibitor is APG-115 or a pharmaceutically acceptable salt or solvate thereof, having the following structure: or solvate thereof:
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(see pages 67-68, claim 6).
14. A method of preventing and/or treating a disease, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a Bcl-2 inhibitor and an MDM2 inhibitor, and the disease is a cancer (see page 69, claim 14).
In addition, the Bcl-2 inhibitor or a pharmaceutically acceptable salt or solvate thereof is administered in an amount from about 0.0025 to 1500 mg/day.
Similarly , the MDM2 inhibitor or a pharmaceutically acceptable salt or solvate thereof is administered in an amount from about 0.005 to 500 mg/day(see page 7 , lines 1-6).
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(see page 61, table 2) (see page 57, a compound 6).
These are identical with the claims.
Conclusion
Claims 21 and 46-56 are rejected.
Claims 1, 19, 39, 54 are objected.
Claims 1, 19 and 39 are withdrawn from consideration.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAYLOR V OH whose telephone number is (571)272-0689. The examiner can normally be reached 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TAYLOR V OH/Primary Examiner, Art Unit 1625 7/17/2026
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