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 .
Status of the Claims
Claims 1-17 are pending.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Instant application is a U.S. National Stage Entry of PCT/CN2021/134454, filed 11/30/2021. PCT/CN2021/134454 claims priority of the foreign applications CN202110167605.X, filed 02/07/2021, CN202011558334.2, filed 12/25/2020, and CN202011386289.7, filed 12/20/2020. Therefore, the effective filing date is 12/20/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/20/2023, 10/16/2023, 05/10/2024, and 07/18/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 16 and 17 are objected to because of the following informalities:
Claims 16 and 17 read “BETA protein-associated disease” and should read “BET protein- associated disease”.
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 1-11 and 13-17 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 compounds of formula (I), (Ib), or (Id) where R1 is C1-3 alkyl; R2 is hydrogen; R3 is -C(O)NHRx; Rx is C1-3 alkyl; R4 is C1-4 hydroxyalkyl; A is a 5- to 6- membered N-containing heterocycle; R5 is hydrogen or halogen; R6 is halogen, C1-3 alkyl, or C3-4 spirocycloalkyl; R7 is halogen, C1-3 haloalkyl, or cyano; m is 0 to 2, and n is 0 to 2, does not reasonably provide enablement for compounds of formula (I), (Ib), or (Id). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
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:
The nature of the invention
The nature of the invention relates to compounds of formula (I) in claim 1. Such compounds are useful as BET protein inhibitors. This invention is also directed to compositions comprising said compounds.
Predictability of the art
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. 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).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
4. The breadth of the claims
The scope of the claims involves compounds of formula (I), shown below.
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Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is a large amount of hypothetical compounds included in claim 1.
5. The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary
The specification only provides the synthesis of 38 compounds. In all of the compounds synthesized, where R2 is hydrogen; R3 is -C(O)NHRx; Rx is C1-3 alkyl; R4 is C1-4 hydroxyalkyl; A is a 5- to 6- membered N-containing heterocycle; R6 is halogen, C1-3 alkyl, or C3-4 spirocycloalkyl; R7 is halogen, C1-3 haloalkyl, or cyano; m is 0 to 2, and n is 0 to 2. Additionally, examples are only provided where R1 is methyl, R5 is chloro-, and X is S. However, it would be assumed that the inventors are also enabled for R1 being ethyl or propyl, for R5 being any halogen, and for X being O, since these substituents are similar in size and reactivity.
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. It would be expected that the varying ring sizes (e.g., where A is an 8-membered ring rather than a 5-membered ring, or where R2 is C6 cycloalkyl rather than hydrogen) and the difference in polarity (e.g., where R6 is alkoxy, halogen, or cyano, rather than alkyl/cycloalkyl) would change the reactivity of the compounds, and therefore would require alternate synthesis methods. It could also be possible that some combinations of compounds may not be able to be synthesized due to their instability (e.g., where m is 6, n is 4, and R1 to R7 contain bulky alkyl or cycloalkyl groups). It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of formula (I) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), 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.
Claims 13 and 15-17 are rejected for being dependent upon a rejected claim and failing to further limit the structure of formula (I).
Claims 16 and 17 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 a method of treating leukemia, does not reasonably provide enablement for the prevention or treatment of any BET protein-associated disease. 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
Breadth of the claims
The breadth of the claim includes a method of treating or preventing any BET protein-associated disease in a patient, comprising administering a compound of the formula (I). BET protein-associated diseases are taught in the instant specification, on page 17, to include tumor diseases, inflammatory diseases, autoimmune diseases, or viral infections.
Nature of the invention
The nature of the invention is performance of a method of treating or preventing a BET-protein associated disease in a patient, comprising administering a compound of formula (I).
State of the prior art
No single drug has been discovered that is effective in treating the myriad of tumor diseases, inflammatory diseases, autoimmune diseases, or viral infections in a patient, including, but not limited to, “a non-solid tumor (for example, leukemia) or a solid tumor (carcinoma and sarcoma), such as acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (comprising monocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia or promyelocytic leukemia), acute T-cell leukemia, B-cell acute lymphoblastic leukemia, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, prostate cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer or non-small cell lung cancer.” See In re Hokum, 226 USPQ 353 (ComrPats 1985).
Level of one of ordinary skill in the art
The artisans performing the inventor’s or joint inventor’s method of preventing or treating a BET protein-associated disease in a patient, comprising administering a compound of formula (I), would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
Level of predictability in the art
Synthetic organic chemistry is quite unpredictable. See In re Marzocchi and Horton 169 USPQ at 367 ¶3. Similarly, it is well established that “[T]he 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).
Amount of direction provided by the inventor
The invention lacks direction with respect to making and/or using (performing) a method of preventing or treating a BET protein-associated disease in a patient, comprising administering a compound of formula (I). No guidance is provided for the prevention or treatment of all BET protein-associated diseases. At best, a therapeutically effective amount is defined in paragraph [0072] as an amount sufficient to “treat or prevent a disease or disorder”, with no guidance on amounts or administration methods needed to prevent or treat any specific BET protein-associated disease.
Existence of working examples
The disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of preventing or treating a BET protein-associated disease in a patient, comprising administering a compound of formula (I).
Similarly, according to the specification, compounds of formula (I) are capable of treating a variety of tumor diseases, inflammatory diseases, autoimmune diseases, or viral infections in a patient, including, but not limited to, “a non-solid tumor (for example, leukemia) or a solid tumor (carcinoma and sarcoma), such as acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (comprising monocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia or promyelocytic leukemia), acute T-cell leukemia, B-cell acute lymphoblastic leukemia, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, prostate cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer or non-small cell lung cancer.”
However, the specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in association with any of the aforementioned diseases. The specification only provides examples for the in vivo treatment of acute myeloid leukemia in a mouse model, comprising administering the example compound 1. There are no examples that show the prevention of any disease, and only the treatment of acute myeloid leukemia is provided in the specification. There is insufficient disclosure to reasonably conclude that the method of preventing or treating a BET protein-associated disease in a patient, comprising administering a compound of formula (I), as recited, would contribute to treatment of any the aforementioned diseases. The inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claim.
Quantity of experimentation needed
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
One skilled in the art, such as a medical doctor, would be required to perform hundreds or thousands of clinical trials and in vivo or in vitro assays in order to determine which compounds of formula (I) would be capable of treating which BET protein-associated diseases, or preventing which BET protein-associated diseases, if prevention is possible.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404. These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for a method of treating a BET protein-associated disease in a patient, comprising administering a compound of formula (I), is clearly justified.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-9, 11, 13, 16, and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2-9, 11, 13, 16, and 17, the phrases “preferably” and “more preferably” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The inventor or joint inventor should note that claims 16 and 17 are reach-through claims. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented. Similarly, the metes and bounds of the preventable or treatable BET protein-associated diseases are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The specification, on page 17, uses open language, such as “includes, but is not limited to”, to define preventable or treatable BET protein-associated diseases as “a tumor disease, an inflammatory disease, an autoimmune disease or a viral infection”, wherein “[i]n some embodiments, the tumor disease includes, but is not limited to, a non-solid tumor (for example, leukemia) or a solid tumor (carcinoma and sarcoma), such as acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (comprising monocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia or promyelocytic leukemia), acute T-cell leukemia, B-cell acute lymphoblastic leukemia, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, prostate cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer or non-small cell lung cancer.”.
However, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments, including, but not limited to, the above listed diseases. Consequently, the method for the treatment or prophylaxis of BET protein-associated diseases, the method comprising administering a compound of formula (I) has been rendered indefinite by the use of the reach-through protocol.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Rejections - 35 U.S.C. § 112(a), to overcome this rejection.
Claims 16 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: the administration of an effective amount of the compound of formula (I) to a patient or subject.
This rejection would be overcome if the claims were written as “a method of treating…comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof…”.
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)(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.
Claim 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by the compound 2-(chloromethyl)-1-(2-chloro-3-thienyl)-1H-benzimidazole (DATABASE REGISTRY [Online] ACS; entered 25 October 2016, XP093184075, Database accession no. 2018805-22-4), cited by Applicant in the IDS.
The compound 2-(chloromethyl)-1-(2-chloro-3-thienyl)-1H-benzimidazole, shown below, reads on instant claim 14, where X is S, R8 is chloro-, R4 and R5 are hydrogen, m is 0, and n is 0.
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Advisory Notice
Claims 12 appears allowable if rewritten in independent form.
Conclusion
Claims 1-11 and 13-17 are rejected.
Claims 12 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 9-5.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624