DETAILED ACTION
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 3, 7, 18, 21-25, 27-32, 35-40, and 42 are pending. Claims 1, 2, 4-6, 8-17, 19, 20, 26, 33, 34, and 41 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/IB2022/055006, filed on May 27, 2022. This application also claims the benefits of foreign priority to IN202141023762, filed on May 28, 2021.
Specification - Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 3 and 24 are objected to because of the following informalities:
For clarity, in claim 3:
“L2 is -C(O)NH-, -C(O)O- or absent” should read“L2 is -C(O)NH-*, -C(O)O-* or absent; wherein * is point of attachment with the phenyl ring”
In claim 24, a period should be added at the end of the sentence.
Appropriate correction is required.
Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the claim set.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Samajdar et al. (Samajdar) (WO 2016/193939 A1; published December 8, 2016).
Novelty:
Samajdar appears to provide the earliest disclosure of the compounds of the instant invention as CDK inhibitors (more particularly, transcriptional CDK7 inhibitors) that are useful in the treatment of diseases and/or disorders associated with selective transcriptional CDKs in a mammal (abstract). In some embodiments, the compounds are useful in the treatment of a variety of cancers including those explicitly listed in the instant claims (Samajdar, pg. 37, last paragraph).
However, Samajdar does not disclose working examples of the instant compounds in combination with an anti-cancer agent for treating cancer in a subject. The experimental support provided in Samajdar is limited to an in vitro TR-FRET assay evaluating the instant compounds’ ability to inhibit CDK7 kinase activity and does not include examples demonstrating combination therapy or co-administration of the instant compounds and an anti-cancer agent in a treatment context.
Thus, the instant invention is considered novel.
Nonobviousness:
Although Samajdar broadly states:
“According to yet another embodiment, the present invention comprises administering to
the subject in need thereof a therapeutically effective amount of a compound of the present
invention along with one or more additional chemotherapeutic agents independently selected
from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain-relieving agents” (pg. 38, 3rd-to-last paragraph)
this disclosure is purely generic. Samajdar does not identify specific anti-cancer agents suitable for combination, does not provide any experimental data supporting combination therapy, and does not teach nor suggest that combination therapy would result in a synergistic or enhanced therapeutic effect of the instant compounds.
Thus, the instant invention is considered nonobvious.
Claim Rejections - 35 USC § 112(a) - Enablement
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 3, 7, 18, 21-25, 27-32, 35-40, and 42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in the MPEP 2164.01(a), “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.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these 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, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a combination of a substituted heterocyclyl derivative of formula (IB):
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or a pharmaceutically acceptable salt thereof which is a CDK7 inhibitor along with an anti-cancer agent or a prodrug thereof, and a method of treating and/or preventing cancer in a subject, comprising administering to the subject a compound of formula (IB) conjointly with the anti-cancer agent.
The variables of general formula (1B) are defined in instant claim 3.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples; amount of direction or guidance present; and quantity of experimentation necessary
The instant claims are directed to a method of treating and/or preventing cancer in a subject, comprising administering to the subject a compound of formula (IB) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, conjointly with an anti-cancer agent.
According to the instant specification, “subject” refers to an animal (pg. 11, lines 4-5) and “treating” means “any treatment of a disease in a mammal, including (a) Inhibiting the disease, i.e., slowing or arresting the development of clinical symptoms; and/or (b) Relieving the disease, i.e., causing the regression of clinical symptoms and/or (c) Alleviating or abrogating a disease and/or its attendant symptoms” (pg. 9, lines 6-9).
However, the instant specification does not provide any in vivo experimental data from animal models or other guidance demonstrating that administration of the instant compounds of Formula (IB) conjointly with an anti-cancer agent, results in a therapeutic effect in an animal.
The disclosure is limited to in vitro data and does not address whether the instant compounds are bioavailable or can reach cancerous tissue in an animal at therapeutically effective levels. The instant specification also does not provide guidance regarding suitable animal models, dosing regimens, routes of administration, or pharmacokinetic considerations necessary to practice the claimed method in vivo.
In the absence of such guidance, a person of ordinary skill in the art would require undue experimentation to determine whether the claimed compounds can be administered to an animal in a manner that produces the claimed therapeutic effect.
Additionally, the specification does not provide any evidence that a cancer can be completely prevented in a subject upon administration to the subject a compound of formula (IB) conjointly with an anti-cancer agent.
The breadth of the claims
The claims are broad insofar as the instant claims recite a method of treating and/or preventing any cancer in a subject comprising administering to the subject a compound of formula (IB), wherein the compound possesses a structurally diverse range of chemical groups, conjointly with an anti-cancer agent.
Claim Rejections - 35 USC § 112(a) – Scope of enablement
Claims 3, 7, 18, 21-25, 27-32, 35-39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Recall from the “Claim Rejections - 35 USC § 112(a) – Enablement” section above that the claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
However, if the specification did enable the subject matter of the instant claims, it would only be enabling for the following:
In regards to a compound of formula (IB):
R2 = C3-C6 cycloalkyl
R3 = H or C1-C6 alkyl
L1 = *-CRcRd-C(O)-; wherein * is point of attachment with the phenyl ring
Rc and Rd are independently H or C1-C6 alkyl
R4 = absent (i.e., m = 0)
L2 = absent
B = monocyclic heteroaryl containing at least one heteroatom wherein the heteroatom is N
R5 =
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R5’ = -(CH2)1-3-NRaRb
wherein Ra and Rb together with the nitrogen atom to which they are attached form an unsubstituted ring containing 0-1 additional heteroatoms independently selected from N, O, or S
R5’’ = H or C1-C6 alkyl
In regards to the cancer being treated:
Breast cancer (including those listed in instant claim 35
Leukemia (including those listed in instant claim 39)
In regards to the anti-cancer agent conjointly administered with a compound of formula (IB):
an estrogen receptor antagonist
an estrogen receptor antagonist wherein the estrogen receptor antagonist is fulvestrant or tamoxifen
a BCL2 inhibitor
a BCL2 inhibitor wherein the BCL2 inhibitor is venetoclax
and the specification would not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above (that is, if the specification did enable the subject matter of the instant claims). 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.
As stated in the MPEP 2164.01(a), “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.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these 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, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
See the “1. The nature of the invention” subsection in the “Claim Rejections - 35 USC § 112(a) – Enablement” section above.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The level of the skill in the art
See the “3. The level of the skill in the art” subsection in the “Claim Rejections - 35 USC § 112(a) – Enablement” section above.
The presence or absence of working examples
The instant specification provides experimental support limited to in vitro combination studies involving compound 44A with either fulvestrant (an estrogen receptor antagonist) or venetoclax (a BCL2 inhibitor). No results from in vivo studies are provided.
Accordingly, the disclosure provides guidance only for in vitro combination use of compound 44A (and at most compounds structurally similar to compound 44A which are compounds comprising the enabled elements listed above) in combination with an estrogen receptor antagonist or a BCL2 inhibitor on MCF-7 cells (i.e., a breast cancer cell line) or Z-138 cells (i.e., a leukemia cell line). The specification does not provide guidance enabling in vitro combination studies with other classes of anti-cancer agents, including aromatase inhibitors, nor does it provide guidance for in vitro combination use with other anti-cancer agents recited in instant claims 29 and 30 on other types of cancer cell lines.
Further, the instant working examples disclosing the therapeutic efficacy of a single compound (i.e., compound 44A) does not provide adequate written description support for the full scope of the instantly claimed methods.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
While compound 44A may be representative of compounds sharing similar structural features (i.e., compounds comprising the enabled elements listed above), it does not reasonably represent compounds falling outside that structural subset such as embodiments wherein L2 is present; ring B is an aryl, cycloalkyl, or a non-heteroaryl heterocycle; R2 is hydrogen or alkyl; R3 is hydrogen, alkyl, or heteroaryl; or R2 and R3 together with the ring atoms to which they are attached form a 5-7 membered ring.
The amount of direction or guidance present and quantity of experimentation necessary
In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to:
make all compounds comprising structural elements that are outside the scope of the enabling elements listed above and
determine which of those compounds, conjointly with an estrogen receptor antagonist or a BCL2 inhibitor, can treat breast cancer or leukemia.
The breadth of the claims
See the “5. The breadth of the claims” subsection in the “Claim Rejections - 35 USC § 112(a) – Enablement” section above.
Claim Rejections - 35 USC § 112(b)
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.
Claim 3 is 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.
Claim 3 recites the limitation “alternatively, R2 together with R1 or R3 along with the ring atoms to which they are attached forms a 5-7 membered ring.” This limitation refers to formula (IB) which does not have a R1 variable. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim 3 also recites the limitation “wherein * is point of attachment with ring A.” This limitation refers to formula (IB) which does not have a “ring A.” Thus, there is insufficient antecedent basis for this limitation in the claim.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3, 7, 18, 21-25, 27-32, 35-40, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-9, 11-13, 16, 18, 21, 22, 24-27 of U.S. Patent Application No. 18/032,919 (‘919)
claim 49 of U.S. Patent Application No. 18/257,962 (‘962)
Claims 1-9, 11-13, 16, 18, 21, 22, 24-27 of ‘919 are directed towards a method of treating or preventing cancer in a subject, comprising administering to the subject a compound of formula (I) (which encompasses a compound of instant formula (IB)) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, conjointly with an anti-microtubule agent. Note: anti-microtubule agents are also considered anticancer agents (see Rowinsky, E. K. et al. Journal of the National Cancer Institute 1990, 82, 1247-1259.; pg. 1247 title, 1st sentence of abstract, and right col.> 1st paragraph> last sentence> taxol is considered an anticancer agent and an antimicrotubule agent). Thus, claims 1-9, 11-13, 16, 18, 21, 22, 24-27 of ‘919 encompass instant claims 3, 7, 18, 21-25, 27, 30, 35, 38, and 39.
Claim 49 of ‘962 is directed towards a method of treating a disease and/or disorder mediated by selective transcriptional CDKs (which includes cancer; see abstract of ‘962) in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) fumarate, as recited in claim 4 of ‘962. It is noted here that Formula (IB) of the instant application encompasses the compound recited in claim 4 of ‘962.
Additionally, the specification of ‘962 states that the compound of formula (I) fumarate may be administered to a subject along with one or more additional chemotherapeutic agents, including anti-cancer agents (pg. 26, lines 20-24). Although claim 49 of ‘962 recites administration of the compound of formula (I) fumarate without explicitly listing the administration of other agents, the transitional phrase “comprising” renders the claimed method open-ended and does not exclude additional steps, such as co-administration of compound of formula (I) fumarate with an anti-cancer agent.
Thus, although the instantly pending claim set and claim 49 of ‘962 are not identical, they are not patentably distinct from each other because there is overlap between the instant claim set and claim 49 of ‘962.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624