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 1-11, 14, 17-19, 22, 23, 27-29, 34, and 39 are pending. Claims 12, 13, 15, 16, 20, 21, 24-26, 30-33, 35-38, and 40-45 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US22/13725, filed on January 25, 2022. This application also claims the benefits of U.S. Provisional Application No. 63/144,287, filed on February 1, 2021.
Information Disclosure Statement
The instant application is accompanied with no IDS. Examiner would like to remind Applicant that “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section. The duty to disclose information exists with respect to each pending claim until the claim is cancelled or withdrawn from consideration, or the application becomes abandoned. Information material to the patentability of a claim that is cancelled or withdrawn from consideration need not be submitted if the information is not material to the patentability of any claim remaining under consideration in the application. There is no duty to submit information which is not material to the patentability of any existing claim. The duty to disclose all information known to be material to patentability is deemed to be satisfied if all information known to be material to patentability of any claim issued in a patent was cited by the Office or submitted to the Office in the manner prescribed by §§ 1.97(b) -(d) and 1.98. However, no patent will be granted on an application in connection with which fraud on the Office was practiced or attempted or the duty of disclosure was violated through bad faith or intentional misconduct.” See 37 C.F.R. 1.56 for more details.
Specification - Abstract
The abstract of the disclosure is objected to because it can be more descriptive. An example of an amended abstract is provided below:
The present invention relates to phosphoinositide 3 kinase beta-selective inhibitors represented by formula (I):
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and pharmaceutical compositions thereof. The variables A, B, W, Rw, R1, R2, and n of formula (I) are as defined herein. Also provided are methods of preparing these inhibitors and using them in therapy of various diseases and conditions, such as solid tumors. Appropriate correction is required.
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 1, 4, 9, 23, 27, and 34 are objected to because of the following informalities:
Claim 1 should read: “Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; which is substituted with one or two substituents each independently selected from the group consisting of halo, NR3aR3b, C1-4 alkyl, OH, OMe and CN;”
In claims 4 and 9:
“indepdently” should be “independently;”
Claim 23 should read:
“…optionally substituted with one or more of…”
For consistency, please use “NR1dR1e” in claim 27 instead of “NR1cR1d.” Claim 27 is dependent on claim 1 which defines the term “C1-4alkyl” as a group that can be substituted with OH, F, and/or NR1dR1e, not NR1cR1d, on pg. 4. Appropriate correction is required.
Claim 34 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 29. See “Claim Rejections - 35 USC § 112(d)” below for more details. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the claims.
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.
112(a) Rejection part 1:
Claims 1-11, 14, 17-19, 22, 23, 27, 29, 34, and 39 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 following enabling elements (from instant claim 1):
A compound having the structural formula (I):
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(I)
wherein
A represents carbon and B represents oxygen, or each of A and B represent nitrogen;
W represents -CHR-Q- or -Q-CHR-; wherein Q represents a bond, CH2, or NR'; R and R' is independently selected from hydrogen or unsubstituted C1-4alkyl;
Rw represents Ar or a substituted or unsubstituted indoline group, wherein Ar is a substituted or unsubstituted phenyl and the substituted indoline or substituted phenyl are substituted with a halogen and/or C1-4alkyl;
R2 represents C1-3alkyl, CH2OH , or CH2F;
R1 represents H, NH2, OH, CN, CH2C(=O)-NR1aR1b, C(=O)-NR1aR1b, CH2COOR1c, NR1dR1e, C1-4alkyl, O-C1-4 alkyl, Het, NR1h(C=O)R1i, NR1j(C=O)NR1kR1l, NR1j(SO2)R1m, SO2NR1nR1o, NR1j(C=O)C(CN)C(OH)R1p
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; provided that, when A is carbon, B is oxygen and Rw is Ar, R1 represents NH2, CN, CH2C(=O)-NR1aR1b, CH2COOR1c, NR1dR1e, O-C2-4 alkyl, Het, NR1h(C=O)R1i, NR1j(C=O)NR1kR1l, NR1j(SO2)R1m, SO2NR1nR1o, or NR1j (C=O)C(CN)C(OH)R1p; when A and B is nitrogen and RW is Ar, R1 represents NR1aR1b or
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wherein R1q and R1r together with the N in which they are bonded to form a 3- to 8-membered nitrogen-containing heterocyclyl ring with one or more substituents selected from the group consisting of C1-3 alkyl and NR3aR3b;
wherein each of R1a, R1b, R1c, R1d, R1e, R1h, R1i, R1j, R1k, R1l, R1m, R1n, R1o, R1p is independently selected from H, C1-4 alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl or C1-4 alkyl substituted with one or more substituents selected from the group consisting of hydroxyl, OMe, CN, fluoro, NR3aR3b, C3-8cycloalkyl, C3-8 heterocycloalkyl; optionally, R1a and R1b, R1d and R1e, and R1n and R1o together with the N in which they are bonded to form a 3- to 8-membered nitrogen-containing heterocyclyl ring with one or more substituents selected from the group consisting of C1-3 alkyl and NR3aR3b;
C1-4 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of OH, F, and NR1dR1e;
R3a and R3b each independently are selected from the group consisting of H, and C1-4 alkyl;
Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl containing at least one heteroatom each independently selected from O, S, S(=O)p and N; which is substituted with one or two substituents each independently selected from the group consisting of halo, NR3aR3b, C1-4 alkyl, OH, OMe, and CN;
n represents 0 or 1; and
p represents 1 or 2;
or a pharmaceutically acceptable form or an isotope derivative thereof
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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.
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 phosphoinositide 3 kinase beta-selective inhibitors represented by formula (I):
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and pharmaceutical compositions thereof. The variables A, B, W, Rw, R1, R2, and n of formula (I) are as defined in the instant specification. Also provided are methods of preparing these inhibitors and using them in therapy of various diseases and conditions, such as solid tumors.
State of the prior art
See sections “Claim Rejections - 35 USC § 102” and “Claim Rejections - 35 USC § 103” below for details.
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 oncology, medicinal chemistry, and/or organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The amount of direction or guidance present and quantity of experimentation necessary
Instant claim 1 recites that Rw of formula (I) can be a substituted group without providing any constraints on the substituents. Therefore, the substituents can be any substituent of any size and made up of any atoms in any structural form. However, the instant specification only discloses 103 exemplified species of formula (I) along with each of their synthetic procedures. In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to make all the compounds of formula (I) wherein the Rw group can be substituted with any substituent.
The presence or absence of working examples
In the instant case, the specification is not fully enabling because it only provides 103 working examples of PI3Kβ inhibitors comprising the enabling elements listed above.
The breadth of the claims
The claims are broad insofar as the instant claims recite a compound represented by formula (I) wherein the compound possesses an Rw that can be a group substituted with any substituent. Note: instant claim 1 does not provide any limitations on the substituents of the Rw group.
Claims 2-11, 14, 17-19, 22, 23, 27, 29, 34, and 39, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are not part of the enabling elements as listed and explained above.
112(a) Rejection part 2:
Claim 39 is 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
See “1. The nature of the invention” section in “112(a) Rejection part 1” above.
State of the prior art
See sections “Claim Rejections - 35 USC § 102” and “Claim Rejections - 35 USC § 103” below for details.
The level of the skill in the art
See “3. The level of the skill in the art” section in “112(a) Rejection part 1” above.
The amount of direction or guidance present and quantity of experimentation necessary
The prior art demonstrates that AZD8186 (a PI3Kβ inhibitor and a homolog of instant compound 24) can treat breast and prostate cancer in mice (in other words, the prior art discloses results from in vivo studies. See Claim Rejections - 35 USC § 103: 103 Rejection – Part 1 below for details). The prior art does not demonstrate a PI3Kβ inhibitor treating a cancer of any type. In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to determine which PI3Kβ inhibitor can treat a cancer of any type.
The presence or absence of working examples
In the instant specification, the term “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated” (pg. 13, para. 0036). In the instant specification, the term “subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment (pg. 13, para. 0035).
Instant claim 39 recites a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to instant claim 1. Based on the definition of “treatment” and “subject” as discussed above, the instant specification, therefore, must show working examples of a cancer being treated (e.g., a cancerous tumor decreasing in volume) in vivo.
The instant specification (pg. 210-216) disclose in vitro studies (i.e., data from cellular and enzyme binding assays) and, therefore, the findings from the in vitro studies cannot enable instant claim 39 since the claim is directed towards a method of treating cancer in a subject.
The breadth of the claims
See “6. The breadth of the claims” section in “112(a) Rejection part 1” above.
Thus, claim 39 is rejected for failing to comply with the enablement requirement.
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 1-11, 14, 17-19, 22, 23, 27, 29, 34, and 39 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.
Claim 1 recites on pg. 3:
“W represents -CHR-Q- or -Q-CHR-; wherein Q represents a bond, O, S, CH2 or NR'; R and R' is independently selected from hydrogen, C1-4alkyl or C1-4alkyl substituted with -OH or halo;”
Claim 1 later recites, on pg. 4, the following:
“C1-4alkyl is unsubstituted or substituted with one or more substituent[s] selected from the group consisting of OH, F [not any halo], [and] NR1dR1e;”
It is unclear what substituents the C1-4alkyl group can be substituted with and, therefore, the metes and bounds of the claim cannot be ascertained and the claim is rendered indefinite.
Claim 1 also recites “… provided that, when A is carbon, B is oxygen and Rw is Ar, R1 represents… COC1-4alkyl…”
The “COC1-4alkyl” substituent contains a carbon atom that does not have a full valency. Examiner is unsure if Applicant intended to state that R1 represents –(C=O)C1-4alkyl or –(CH2)OC1-4alkyl. Therefore, the metes and bounds of the claim cannot be ascertained and the claim is rendered indefinite.
Claim 17 recites:
“The compound of claim 1, wherein W-Rw is selected from:
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…”
There is insufficient antecedent basis for this limitation in the claim. Claim 17 depends on claim 1 which does not mention that Rw can be:
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or
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. Claim 1 says Rw is Ar which is a substituted or unsubstituted 6-membered aromatic or hetero-aromatic or an unsubstituted or substituted indoline group. The four pyrrolidine-pyridinyl rings are not indoline. Indoline has the following structure:
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(see Millipore Sigma indoline product page attached to file wrapper by Examiner). Furthermore, the instant specification states:
“‘hetero-aromatic’ as used herein, means a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. The monocyclic heteroaryl ring is a 5- or 6- membered ring. The 5-membered ring has two double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S. The 6-membered ring has three double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S. The bicyclic heteroaryl ring consists of the 5- or 6-membered heteroaryl ring [Note: which, according to the previous sentences, the 5-membered ring must have two double bonds; however, the 5-membered ring fused to the pyridinyl or the 5-membered ring in indoline only has one double bond that is shared between the two rings] fused to a phenyl group [Note: not a pyridinyl group] or the 5- or 6-membered heteroaryl ring fused to a cycloalkyl [not a heterocycloalkyl] group or the 5- or 6-membered heteroaryl ring fused to a cycloalkenyl [not a heterocycloalkenyl] group or the 5- or 6-membered heteroaryl ring fused to another 5- or 6-membered heteroaryl ring” (pg. 16-17, para. 0046).
Thus, indoline,
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and
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are not classified as hetero-aromatic rings as defined by the instant specification and the claim is rendered indefinite.
Claim 17 further recites “wherein R is independently selected from hydrogen, C1-4alkyl or C1-4alkyl substituted with OH or halo.” Claim 17 depends on claim 1 which defines the term “C1-4alkyl” (on pg. 4) as a group that can be substituted with OH, F (not any halo), and/or NR1dR1e. It is unclear what substituents the C1-4alkyl group can be substituted with and, therefore, the metes and bounds of the claim cannot be ascertained and the claim is rendered indefinite.
Claim 23 recites the limitation “…wherein R1q and R1r together form a 3- to 8-membered nitrogen-containing heterocyclyl ring optionally substituted with one [or] more of C1-3alkyl and NR3aR3b.” There is insufficient antecedent basis for this optional limitation in the claim. Claim 23 depends on claim 1 which states on pg. 4: “…wherein R1q and R1r together form a 3- to 8-membered nitrogen-containing heterocyclyl ring with one or more substituent[s] selected from the group consisting of C1-3alkyl and NR3aR3b.” Claim 1 does not state that the 3- to 8-membered nitrogen-containing heterocyclyl ring can be optionally substituted with C1-3alkyl and/or NR3aR3b. Therefore, the claim is rendered indefinite.
Claim 27 recites the limitation “…wherein R1 is C1-4alkyl, optionally substituted with hydroxy, -O-C1-4alkyl, and NR1cR1d.” There is insufficient antecedent basis for this optional limitation in the claim. Claim 27 is dependent on claim 1 which defines the term “C1-4alkyl” as a group that can be substituted with OH, F, and/or NR1dR1e on pg. 4. It does not state that C1-4alkyl can be substituted with an -O-C1-4alkyl group. It is unclear what substituents the C1-4alkyl group can be substituted with and, therefore, the metes and bounds of the claim cannot be ascertained and the claim is rendered indefinite. Further, Examiner would like to make a note that currently, claim 27 stating “…wherein R1 is C1-4alkyl, optionally substituted with hydroxy, -O-C1-4alkyl, and NR1cR1d” implies that if R1 is substituted, it must be substituted with all three of the following: hydroxy, -O-C1-4alkyl, and NR1cR1d. If this is not what the Applicant intended for the claim to be interpreted as, Examiner suggests that the claim be amended as follows:
“The compound of claim 1, wherein R1 is C1-4alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, -O-C1-4alkyl, and NR1cR1d.”
Claims 2, 3, 5, 7, 8, 10, 14, 18, 19, 22, 29, 34, and 39, which are dependent on claim 1 and/or any of the other aforementioned claims that are rendered indefinite, are also rejected for further requiring and/or reciting the indefinite limitations of the claim(s) in which they are dependent upon.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 34 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Instant claim 34 is directed towards a unit dosage form comprising a pharmaceutical composition that contains a compound of instant formula (I) and a pharmaceutically acceptable excipient with no additional components specified. Therefore, the claim language of instant claim 34 suggests that the unit dosage form can be identical to the pharmaceutical composition of instant claim 29. Therefore, claim 34 is not further limiting the subject matter of the claim upon which it depends and is, in fact, a duplicate of claim 29.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Note on 35 USC § 102 and § 103 Rejections
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(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.
Claims 1, 7-9, 14, 18, 23, 29, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Barlaam et al. (Barlaam) (Barlaam, B. et al. Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours. Bioorg. Med. Chem. Lett. 2014, 24, 3928-3935.)
Barlaam discloses a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a] pyrimidine-7-carboxamides as potent and selective PI3K (i.e., phosphoinositide-3-kinases) β and δ inhibitors (abstract). A specific example of a PI 3-kinase β and δ inhibitor is compound 24 (herein, referred to as compound-24-Barlaam; pg. 3931, Table 3, structure reproduced below):
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. Compound-24-Barlaam is a species of instant claim 1 wherein:
A is nitrogen and B is nitrogen,
W = -CHR-Q- (wherein R = unsubstituted C1 alkyl; Q = NR’ wherein R’ = H),
Rw = Ar (wherein Ar is a substituted phenyl that is substituted with two fluoro substituents),
n = 0 (indicating R2 is absent) and
R1 is C(=O)-NR1qR1r (wherein R1q and R1r together form a 6-membered nitrogen-containing heterocyclyl ring that is substituted with an unsubstituted C1alkyl)
and anticipates instant claims 1, 7-9, 14, 18, and 23.
According to Barlaam Table 3, the Log D7.4 of compound-24-Barlaam was measured using shake-flask methodology (see footnote c) with a buffer/octanol volume ratio of 100:1 (see footnote 18 on pg. 3935). “The concentration of compound in the aqueous phase before and after partitioning with octanol was determined by generic HPLC analysis” (pg. 3935, footnote 18). In other words, Barlaam discloses a composition comprising at least compound-24-Barlaam and water (from the aqueous phase). Note: water is a known pharmaceutically acceptable excipient (Allen, L. V. Sterile Basics: Pharmaceutical Waters Used in Sterile and Nonsterile Compounding. Int J Pharm Compd. 2019, 5, 399-402.; abstract). Thus, this composition anticipates instant claims 29 and 34.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7-9, 14, 18, 19, 23, 28, 29, 34, and 39 are rejected under 35 U.S.C. 103.
103 Rejection – Part 1:
Claims 1-4, 14, 18, 28, 29, 34, and 39 as being unpatentable over:
Hancox et al. (Hancox, U. et al. Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel. Mol Cancer Ther 2015, 14, 48-58.
Hancox discloses a PI3Kβ inhibitor, compound AZD8186, of the following structure:
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(pg. 51, Figure 1A). According to Hancox, “[i]n the PTEN-null line, MDA-MB-468, AZD8186 inhibited PI3Kβ-dependent activation of pAKT (Ser473) with an IC50 value of 3 nmol/L… These data show that in cells, AZD8186 is a potent inhibitor of PI3Kβ” (pg. 50, right col., “Results” section, 7th sentence and 2nd to last full sentence). Hancox further discloses data “establish[ing] that AZD8186 is capable of modulation PI3K pathway activation in PTEN-null TNBC and prostate tumor models, resulting in decreased tumor growth [in vivo]” (pg. 53, section “AZD8186 modulates pathway biomarkers and inhibits growth of breast and prostate tumor models,” right col., last paragraph, 2nd to last sentence). In other words, Hancox demonstrates that AZD8186 can treat breast and prostate cancer in mice. See pg. 53, “AZD8186 modulates pathway biomarkers and inhibits growth of breast and prostate tumor models” section for details on the in vivo studies disclosed by Hancox.
Note: AZD8186 is NOT a species of instant claim 1. According to instant claim 1, when A is carbon, B is oxygen, and Rw is Ar, R1 being C(=O)-NR1aR1b (wherein R1a = R1b = Me) is not an option. There is only an option for R1 being -CH2C(=O)-NR1aR1b. Instant compound 24 (see instant claim 28 on pg. 10 of the claim set) is a species of instant claim 1 AND is a homolog of AZD8186:
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(Note: the C(=O)N(Me)2 group in AZD8186 is replaced with its homolog, the CH2(C=O)N(Me)2 group [highlighted in yellow] in instant compound 24). Therefore, instant compound 24 is expected to have properties that are similar to AZD8186. It is further noted here that AZD8186 is also a compound that is being tested in a phase I clinical trial as of 2015 (pg. 57, right col., 2nd paragraph, last sentence).
According to MPEP 2144.09:
I. REJECTION BASED ON CLOSE STRUCTURAL SIMILARITY IS FOUNDED ON THE EXPECTATION THAT COMPOUNDS SIMILAR IN STRUCTURE WILL HAVE SIMILAR PROPERTIES
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c).
II. HOMOLOGY AND ISOMERISM ARE FACTS WHICH MUST BE CONSIDERED WITH ALL OTHER RELEVANT FACTS IN DETERMINING OBVIOUSNESS
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Hancox discloses that “AZD8186 inhibits pAKT (Ser473 and Thr308) and pPRAS40 [in vivo] following acute or chronic dosing in HCC70 (Fig.3B–D) and MDA-MD-468 (Fig. 3F–H) in a dose- and time-dependent manner” (pg. 53, left col., last sentence). In the instant application, the inhibition of phosphorylation of AKT at Ser473 in HCC70 cells, in vitro, was also measured. As expected, the inhibition of p-AKT (Ser473 and Thr 308) activity was very high (i.e., Index is >90%; see bottom of pg. 210 of instant specification for the formula used to calculate the index) for instant compound 24 (instant specification, pg. 211, Table 1).
Hence, instant claims 1-4, 14, 18, 28, and 39 are rendered obvious.
For the in vivo experiments disclosed in Hancox, “AZD8186 was generally formulated once weekly as a suspension in HPMC/Tween and dosed once or twice daily (0 and 6–8 hours). For groups in which ABT was administered, AZD8186 was formulated once weekly either alone in 10% DMSO/60% triethylene glycol (TEG)/30% water for injection (WFI) or in the presence of ABT at 10 mg/mL” (pg. 50, left col., 2nd to last paragraph, 1st and 2nd sentences). Therefore, one of ordinary skill in the art would have also found it obvious to formulate a homolog of AZD8186 (such as instant compound 24) in the same manner. Hence, instant claims 29 and 34 are also rendered obvious.
103 Rejection – Part 2:
Claims 1, 7-9, 14, 18, 19, 23, 29, and 34 as being unpatentable over:
Barlaam et al. (Barlaam) (Barlaam, B. et al. Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours. Bioorg. Med. Chem. Lett. 2014, 24, 3928-3935.)
Barlaam et al. (Barlaam-2015) (Barlaam, B. et al. Discovery of (R)‑8-(1-(3,5-Difluorophenylamino)ethyl)‑N,N‑dimethyl-2-morpholino-4-oxo‑4H‑chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers. J. Med. Chem. 2015, 58, 943-962.)
The teachings of Barlaam as they apply to claims 1, 7-9, 14, 18, 23, 29, and 34 are as discussed in “Claim Rejections - 35 USC § 102” and incorporated herein. Additionally, given that the claimed invention (as described by claims 1, 7-9, 14, 18, 23, 29, and 34) is anticipated by the prior art, a POSITA would have found it obvious to reproduce the subject matter disclosed in Barlaam.
Barlaam does not teach a PI3Kβ inhibitor wherein the morpholine group is substituted with a methyl group. Barlaam-2015 is relied upon for this disclosure.
Barlaamm-2015 discloses a derivative of compound 13 (compound 13 is disclosed in pg. 949, Table 2) wherein the morpholine group is substituted with a methyl group (see pg. 950, Table 4, compounds 35-1 and 36-1). Note: compound 13 is a racemic mixture of AZD8186 and its enantiomer. According to Barlaam-2015, “35-1 showed increased potency on PI3Kα and PI3Kβ (∼7-fold) compared to 13, whereas 36-1 was slightly less potent both on PI3Kα and PI3Kβ (∼4-fold). All three compounds maintained the same high degree of selectivity (∼200−300-fold) between the two isoforms” (pg. 952, left col., paragraph right below Figure 3, last two sentences).
Therefore, one of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to modify the morpholine group in compound-24-Barlaam with a methyl substituent:
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. One of ordinary skill in the art would have been motivated to make this modification since Barlaam-2015 has shown that inclusion of a methyl substituent on the morpholine group of compound 13 can dramatically affect the compound’s potency on PI3Kα and PI3Kβ (i.e., increase in potency when the carbon in morpholine bonded to the methyl has an (R) stereocenter [compound 35-1] and decrease in potency when the carbon has an (S) stereocenter [compound 36-1]; pg. 952, left col., paragraph right below Figure 3, last two sentences). Thus, instant claim 19 is rendered obvious.
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