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 .
This is a Final Office Actions.
Claims 1, 2, 4, 7, 8, 10, 14, 16, 17, 20, 24-27, 29, 37, 38, 41 and 46 are pending and under examination.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) (PROVISIONAL) or 119(a) (FOREIGN) or under 35 U.S.C. 120 (CONT/CIP), 121(DIV), or 365(c) (WO) is acknowledged.
Claim Objections
The objection to claim 1 because the term “or” should be replaced between the last two groups in the definition of Ra, is withdrawn based on the amendments.
The objection to claim 18 because the claim is the same scope as claim 1, is withdrawn based on the amendments.
Claims 2, 4, 8, 10, 14, 16, 20, 25, 27, 29, 37 and 38 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The rejection of claims 17, 24 and 26 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for a lack antecedent basis with regards to the “oxo” substituent in the definition of R3, is withdrawn based on the amendments.
The rejection of claim 37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for referring to the specification is withdrawn based on the amendments.
The rejection of claim 46 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the broad recitation gastro-intestinal tumors, and the claim also recites GIST, is withdrawn based on the amendments.
The rejection of claim 46 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the broad recitation dysproliferative changes, and the claim also recites “dysplasia and metaplasias”, is withdrawn based on the amendments.
The rejection of claim 46 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the broad recitation solid tumors, and the claim also recites “carcinomas and sarcomas”, is withdrawn based on the amendments.
The rejection of claim 46 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the broad recitation chronic myelocytic, and the claim also recites “granulocytic”, is withdrawn based on the amendments.
The rejection of claim 46 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the broad recitation acute myelocytic leukemia, and the claim also recites “monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic”, is withdrawn based on the amendments.
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 1, 7, 17, 24 and 26 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 pre-AIA the applicant regards as the invention.
Regarding claims 1 and 17, the phrase in claim 1, “the heterocycloalkyl and heteroaryl” in the definition of Ra is vague, see page 2, the 3rd and 4th line from the bottom of the page. There is more than one heterocycloalkyl and heteroaryl in the definition of Ra. Does the wherein clause refer to one or more than one? The same is found for alkyl in the definition of R3 and R4 in claims 1, 17 and 18.
Applicant states, “Claims 1 and 17 as amended recite the phrase "each" before "heterocycloalkyl", and "heteroaryl" and "alkyl." Therefore, the wherein clauses in the present claims refers to each of the heterocycloalkyl, heteroaryl, or alkyl.”
The amendment does not overcome the rejection. The “each” may be applied to each group. The claim may be amended by removing the term “the” after the wherein clause to overcome the rejection. Thus, the rejection is maintained over claims 1 and 17/
With regards to claims 7, 24 and 26, all of the azabicyclo or azaspiro rings in each of these claims are substituted with an oxo group and therefore cannot have an additional 3 substituents substituted on the rings. This would exceed the number of substituents in claim 1. Thus, the claims are vague.
Applicant states, “Without conceding the accuracy of the Examiner's interpretation, Applicant asserts that the present claims refer to oxo as an optional substitution. Therefore, one of ordinary skill in the art would readily understand that the recited substituents are only applicable to positions on the azabicyclo or azaspiro rings where such substitution is chemically and structurally permissible, and within the limits set forth in claim 1.”
Please note the specific azabicyclo rings in claim 7 that already have an oxa substitution in the name. These rings cannot have an additional 3 substituents. Therefore, the rejection is maintained.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 41 and 46 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 the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes, does not reasonably provide enablement for cancer, fibrosis, inflammation, or an inflammatory disease, generally. 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.
The treatment of cancer, fibrosis, inflammation, or an inflammatory disease, generally cannot possibly be considered enabled. Moreover, treatment is defined as abrogation, which can be prevention, on page 50 pf the specification.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification 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, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(A) Breadth of claims.
(a) Scope of the compounds. The instant claims encompass millions of compounds of formula (I) with a variety of substituents at eight different positions.
(b) Scope of the diseases covered. The scope was provided in the previous office action and is incorporated here.
The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for cancer, fibrosis, inflammation, or an inflammatory disease, generally.
(B) The nature of the invention and predictability in the art: With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. 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).
(C) Direction or Guidance: That provided is very limited. The dosage range information is not found in the specification. On pages 53-54, the specification states, “Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.” This is generic. Moreover, this is broad, the same for the many disorders covered by the specification. Thus, there is no specific direction or guidance regarding a regimen or dosage effective specifically for cancer, fibrosis, inflammation, or an inflammatory disease, generally.
(D) State of the Prior Art: The claimed compounds are compounds of formula (I). So far as the examiner is aware compounds of formulas (I) have not been successfully used to treat cancer, fibrosis, inflammation, or an inflammatory disease, generally.
The prior art has established that there is no common mechanism by which all, or even most, inflammations arise. Mediators include bradykinin, serotonin, histamine, fibrin, PDE-IV, kallikrein, plasmin, thrombin, PAF, Mac-1, VLA-4, VLA-5, VLA-6, VCAM-1, LFA-1, ICAM-1, Prostaglandins and cyclic endoperoxides (particularly prostacycline, prostaglandin E2, and thromboxane A2), leukotrienes (especially LTB4, LTC4, LTD4, and LTE4) and cytokines, and many, others. Examples of pro-inflammatory cytokines include IL-1I, IL-1J, IL-6, IL-8, IL-18, MIP-1a, IFN-K and TNF-I. The Complement Pathway, which exists in two separate branches, uses C1, C4a, C4b, C2, C3a, C3b, C5a, C5b, C6, C7, C8 and C9, as well as the membrane attack complex (MAC) and other complexes, C3 and C5 convertase enzymes, Magnesium ions, and Factors B, D, F, H, etc.
The prior art knows that mediation of inflammation is among the most pervasive and complex of all body process. There are complex interactions among just the cytokines, and just in certain types of inflammatory responses. As a second example, the Hageman factor is a protein that initiates three different processes: a) the intrinsic clotting process, which operates via thrombin and fibrin, b) the fibrinolytic system which produces fibrinolysis via plasmin and 3) the kallikrein/kinin cascade, which produces the kinins, e.g. bradykinin. Further, Plasmin can also activate C3 and C5 in the complement cascade (an entirely separate set of vascular events) producing C3a and C5a, respectively, as can thrombin.
Further, the prior art knows that there are many paradoxical features in the inflammation system. As an example, in lung inflammation, nitric oxide appears to be a pro-inflammatory mediator in acute situations e.g. ARDS but anti-inflammatory in more stable situations. As a second example, the cytokine TGF-beta-1 possesses both pro-inflammatory and anti-inflammatory activities. Virtually all cells have TGF-beta-1 receptors, and the cytokine has many other roles other than in inflammation. As a third example, CRF appears to have both pro-inflammatory and anti-inflammatory activities.
Thus, the prior art knows that, treatments for inflammation are normally tailored to the particular type of inflammation present, as there is no, and there can be no "magic bullet" against inflammation generally.
(E) Working Examples: The invention is drawn to a method of treating cancer, fibrosis, inflammation, or an inflammatory disease, generally. There are no in vivo working examples in the specification drawn to this utility to support the use of compounds of formula (I) to treat any and all cancer, fibrosis, inflammation, or an inflammatory disease, generally. On pages 208-2013 of the specification there are several in vitro assays presented which provide data for the inhibition of CREBBP; inhibition of P300 enzyme; and inhibition of BRD4 FL.
(F) Skill of those in the art: The skill level in the art was provided in the previous office action, which still applies here.
(G) The quantity of experimentation needed: Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors A and D and F, the quantity of experimentation needed is expected to be great.
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.
Applicant traverses by stating 1) Claims 41 and 46 require that the disease or disorder is CBP and/or EP300-mediated; 2) The present application discloses the importance of the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes in the context of cancer, fibrosis, inflammation, or an inflammatory disease, generally; and 3) One of skill in the art would understand that the inhibition of CREBBP, EP300 and/or
BRD4 FL would enable the scope of claims 41 and 46.
This is not persuasive.
The phrase “CBP and/or EP300-mediated disease or disorder” is cited in claims 41 and 46, and claim 46 further defines some of those diseases and disorders. Claim 41 also embraces those diseases and disorders defined in the specification as being a CBP and/or EP300-mediated disease or disorder. However, even the narrower scope of the diseases and disorders in claim 46 cannot be considered enabled. The plethora of diseases and disorders cited have not been shown to be treated by the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes.
Applicant states, “Accordingly, the claims are not directed to the treatment of all diseases falling under the general categories of "cancer," "fibrosis," or "inflammation," but only to those mediated by CBP and/or EP300 as featured in claim 41. The Examiner's rejection is therefore based on an interpretation that is inconsistent with the actual claim language and improperly broadens the scope of the claims beyond what is recited.” The application has not shown support where these diseases and disorders can be treated by the inhibition of the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes.
Applicant further states, “The Examiner asserts that, under In re Wands, 858 F.2d 731 (Fed. Cir. 1988), the claims are broad in view of the number of possible compounds and the number of diseases encompassed. NFOA, p. 9. The Examiner goes on to list the causes, mechanisms, and treatment for cancer, fibrosis, inflammation, or an inflammatory disease, generally. NFOA, p. 9-29. However, this analysis rests on an incorrect premise regarding the breadth of the claims. The Examiner's characterization of the disease scope as encompassing "hundreds of cancers" or broadly "any inflammatory disease" is not consistent with the actual claim language. The Wands factor concerning claim breadth must be assessed in light of the true, limited scope of the claims as drafted. See In re Fisher, 427 F.2d 833, 839 (C.C.P.A. 1970) (the enablement inquiry "must be commensurate in scope with the claims").” As noted previously, claim 41 embraces those diseases and disorders that have been defined in the specification also.
Applicant further notes, “The Examiner later cited the Enablement Decision Tree from the USPTO website, alleging that "the prior art knows that there never has been a compound capable of treating cancers generally." NFOA, p. 33 at 2ⁿᵈ 1. Applicant does not disagree that a "single compound" may not be capable of treating all cancers generally. However, the present claims are not directed to treating "cancers generally," but rather target a very specific mechanism in the claimed indications (i.e. CBP and/or EP300-mediated diseases or disorders) and are therefore not relevant in the context of the cited example.” Again, the application does not support the treatment of the full scope of diseases and disorders identified as being mediated by CBP and/or EP300. Moreover, the art does not support the scope of the disease and disorders in the narrower claim 46, either.
Applicant further notes, “As-filed specification, p. 1-2. The paragraphs above describes CREBBP and EP300 as transcriptional co-activators in human cells that catalyze the attachment of an acetyl group to a lysine side chain of histones and other protein substrates. Given the relationship between the acetylation of histones in gene activation, modulation of both CREBBP and EP300 would be pivotal in therapies for conditions where gene activation plays a role, i.e. cancer, fibrosis, inflammation, inflammatory disease, etc.” There are many different proteins involved in many diseases and disorders but not all are successfully targeted for the treatment of diseases and disorders.
Applicant states, “The Examiner alleged that dosage guidance in the specification is "generic" and lacks disease-specific direction. NFOA, p. 30 at 2ⁿᵈ 1. Applicant respectfully submits that this conclusion does not take into account the mechanistic limitation of the claims to CBP and/or EP300-mediated diseases or disorders. The specification discloses a great amount of direction for the synthesis of
the compounds claimed in claim 1, as exemplified throughout the specification. One of ordinary skill in the art would understand that these teachings, together with knowledge of pharmacology, pharmacokinetics, pharmacodynamics, and established dose-ranging methodologies, provide sufficient guidance to determine appropriate regimens for the claimed disease states without undue experimentation.” The statement regarding dosage does take into account all the claim limitations and is based on what is disclosed.
Applicant contends, “Lastly, the results shown in pages 209-213 of the as-filed specification provide examples of 1) the potency of the compounds to inhibit CREBBP enzyme as tested in a TR-FRET displacement assay using recombinant CREBBP bromodomain (Example-P1); 2) the potency of the claimed compounds to inhibit P300 enzyme as tested in a TR-FRET displacement assay using recombinant P300 bromodomain (Example-P2); and 3) the potency of the claimed compounds to inhibit BRD4 FL enzyme as tested in a TR-FRET displacement assay using recombinant BRD4 FL bromodomain (Example-P3). As mentioned previously, the Office has acknowledged the specification is enabled "for the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes." Indeed, the specification is enabled for "for the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes." What is missing is the nexus between the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes and the treatment of the diseases.
Applicant further contends, “The Examiner alleged that "there is substantive 'reason for one skilled in the art to question the objective truth of the statement of utility or its scope' (In re Langer, 183 USPQ 288, 297)." NFOA, p. 34 at 3rd . Applicant traverses this assertion since it appears to be based on Langer and In re Novak, 134 USPQ 335, 337-338. Applicant reiterates that the Examiner's reasoning in this case relies on the premise that the claims are directed to any cancer, fibrosis, inflammation, or inflammatory disease. This premise is incorrect. Claims 41 and 46 are expressly limited to CBP and/or EP300-mediated diseases or disorders, and are not directed to all cancers, all inflammatory diseases, or all fibrotic conditions.
The results shown in Examples P1, P2, and P3 as discussed clearly demonstrate experimental evidence that the claimed invention is successful in inhibiting CREBBP, EP300, and BRD4 FL enzymes. It follows that one of ordinary skill in the art would understand that inhibition of these enzymes is predictive of therapeutic benefit in diseases mediated by CBP and/or EP300. Langer and Novak are based on scenarios where one of ordinary skill in the art would question the statement of utility or its scope. However, in this case, as demonstrated above, there is a direct link between the disclosure and the claimed method. The claims are directed to disease mediated by enzymes, which Applicant has successfully been able to inhibit in exemplary embodiments of the invention.
Furthermore, one of skill in the art would understand that the inhibition of CREBBP, EP300, and BRD4 FL enzymes in general is expected to modulate CBP- and/or EP300-mediated diseases. It is known that these enzymes regulate transcription of genes involved in cell proliferation, extracellular matrix production, and inflammatory signaling, and can therefore modulate the disease processes that lead to CBP- and/or EP300-mediated cancer, fibrosis, or inflammation. Accordingly, compounds inhibiting these enzymes are reasonably expected to have a therapeutic effect in CBP- and/or EP300-mediated diseases or disorders, without requiring disease-specific in vivo data for each condition.
Thus, one of ordinary skill in the art would understand from the disclosure and the well- established literature that inhibition of CREBBP, EP300, and BRD4 FL provides a credible and practical approach to treating CBP- and/or EP300-mediated diseases or disorders.” Again, the specification is enabled for "for the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes." What is missing is the nexus between the inhibition of CREBBP, EP300 and/or BRD4 FL enzymes and the treatment of the diseases.
Thus, the rejection is maintained.
To overcome the rejection, claim 41 may be amended to the mode of action, i.e. a method of inhibiting CREBBP, EP300 and/or BRD4 FL enzymes, and claim 46, with the currently claimed diseases and disorders, may be dependent from claim 41.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 2, 7, 10, 14 and 16-18 under 35 U.S.C. 102(a)(1) as being anticipated by PubChem (compound SID 407279066 and CID 146884776, available August 12, 2020, see the IDS dated May 14, 2025), is withdrawn based on the amendments.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 2, 4, 7, 10, 14, 16-18, 38, 41 and 46 under AIA 35 U.S.C. 103(a) as being unpatentable over Cyr et al. (US 20190152949), is withdrawn based on the amendments.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624