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 1-4, 7, 10, 13, 16, 18, 19, 26, 31, 34, 43, 53-55, 61, and 74 are pending. Claims 5, 6, 8, 9, 11, 12, 14, 15, 17, 20-25, 27-30, 32, 33, 35-42, 44-52, 56-60, 62-73, 75-88 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2023/061241, filed on January 25, 2023. This application also claims the benefits of priority to U.S. Provisional Application No. 63/302,858, filed on January 25, 2022.
Specification - Abstract
The abstract of the disclosure is objected to because it is not in compliance with 37 C.F.R. 1.72 (b). Specifically, the sheet presenting the abstract includes other parts of the application or other material. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
For clarity, please ensure that the amended abstract still includes the general structure of instant Formula (I).
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.
Drawings Objections
The drawings are objected to because multiple figures, graphs, tables, and/or diagrams are presented on each page at a size that renders the accompanying text and labels blurry or otherwise illegible. With respect to pages 1-16 of the Figures document (which encompasses Figures 1A-16G), Applicant is required to redistribute the figures over additional pages so that each figure, graph, table, and/or diagram is reproduced at a sufficiently large scale to ensure that all text, labels, symbols, and data are clearly legible. Applicant should limit each page to no more than four figures/graphs/tables/diagrams to preserve legibility.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 2 are objected to because of the following informalities:
Currently, claims 1 and 2 recite:
“L2 and L3 is… -NRaC(O)-, -NRaC(O)-, …”
Note: “-NRaC(O)-,” appears twice.
For clarity and to not be repetitive, one of the “-NRaC(O)-,” can be removed
OR
if the second “-NRaC(O)-“ was intended to be “-C(O)NRa-“ instead, please correct it accordingly.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 1-4, 7, 10, 13, 16, 18, 19, 26, 31, 34, 43, 53-55, 61, and 74 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 compound having the formula:
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wherein
R1 = pyrrolyl, pyrazolyl, thiophenyl, or methyl-substituted version of any of these groups,
R2 = R2’ = Me,
R3 = -CH2-phenyl (wherein the phenyl is substituted with F or CF3),
X1 = NH
A1 = phenyldiyl, oxazoldiyl, or thiazoldiyl,
L1 = covalent bond, -NHC(O)-, -C(O)NH-, or -C(O)O-,
R4 =
C1-C6 alkyl optionally substituted with OH or halo,
Unsubstituted C2-6 alkenyl,
Unsubstituted C2-6 alkynyl,
Halo,
Unsubstituted C1-6 alkoxy,
H, or
Unsubstituted C3-6 cycloalkyl
OR
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is
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or
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;
A pharmaceutical composition comprising an excipient and a compound of point (1) above;
A method of treating pancreatic cancer, colorectal cancer, or lung cancer in a patient in need thereof comprising administering to the patient an effective amount of a compound of point (1) above;
The method of point (3) above further comprising administering to the patient an effective amount of an alkali earth metal salt or an aqueous solution 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 to make and use the invention based on the content of the disclosure, 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 compounds of the formula (I):
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wherein the variables are defined in the instant specification, as well as pharmaceutical compositions thereof. The present disclosure also provides methods of inhibiting isocitrate dehydrogenase 1 (IDH1) and methods of treating or preventing a disease or disorder using said compounds and/or compositions.
State of the prior art
Prior art referenced:
Winter (WO2021071678A1; published April 15, 2021)
The prior art discloses that while the prior art compound (i.e., AG-120, an inhibitor of mutant IDH1 enzyme: see abstract of Winter) “target the wild type enzyme at any glucose condition when magnesium levels are low, they only impact cancer cell survival when nutrients are also low” (pg. 22, lines 24-25). Therefore, the prior art teaches that successful wild-type IDH1 inhibition does not necessarily produce a therapeutic effect under any condition because the effect depends on the biological context.
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 breadth of the claims
The instant claims are broad insofar as they encompass an extremely large genus of compounds comprising substituents that can itself be substituted with any substituent. The claims do not limit the chemical structure of what these substituents can be substituted with. The claims likewise do not place any meaningful structural limitations on the recited ubiquitin ligase ligand or fluorophore. Consequently, these variables encompass an extraordinarily diverse set of chemically distinct moieties possessing substantially different molecular architecture, size, geometry, and binding characteristics.
The method claims are also extremely broad insofar as they encompass treatment of all diseases and disorders. A POSITA understands that all existing diseases and disorders include those with diverse and unrelated molecular mechanisms as well as those that are not established as being dependent on wild-type IDH1 activity.
The presence or absence of working examples
The instant specification only provides 30 specific examples of compounds encompassed by instant claim 1 (see instant specification, pg. 51-57). The working examples do not adequately represent the full breadth of the claimed genus which was established to be extremely broad (see “4. The breadth of the claims” subsection above). The instant compounds all fall within a much narrower scope as defined above (i.e., the enabling elements). Accordingly, significant portions of the claimed structural space remain unexplored by the working examples. The examples, therefore, provide only limited information regarding how slight variations in the variables affect wild-type IDH1 inhibitory activity (see instant Example 1 for data) across the full scope of the claimed genus.
Additionally, the working examples do not adequately represent the full breadth of the claimed methods of treatment. The instant specification demonstrates therapeutic efficacy of AG-120 (a previously-known, potent wild-type IDH1 inhibitor under low Mg2+ conditions: see instant specification, para. 0042, 1st sentence) in pancreatic, colorectal, and lung cancer models (instant specification, para. 0046 and 0048). The instant specification also demonstrates therapeutic efficacy of one of the instant compounds in a pancreatic cancer model (see Fig. 16f). However, the instant specification does not provide working examples demonstrating therapeutic activity in all diseases and disorders. The instant specification also does not provide any generally applicable guidance or predictive basis from which a POSITA could reasonably conclude that the demonstrated therapeutic efficacy in pancreatic, colorectal, and lung cancer would extend to the full range of diseases and disorders encompassed by the claims.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
Claims 61 and 74 broadly encompasses treating any “disease or disorder” in a patient by administering an effective amount of a compound within the recited genus. However, the specification provides therapeutic evidence primarily for particular cancer models (i.e., pancreatic, colorectal, and lung cancer; see instant para. 0046 and 0048) and expressly recognizes that the effectiveness of wild-type IDH1 inhibition depends on specific biological conditions. In particular, the specification states that the disclosed drugs become potent inhibitors of wild-type IDH1 “only under specific conditions present in tumors: low glucose when wtIDH1 is critical for PC cell survival and low magnesium which is required for effective allosteric inhibition of the wtIDH1 isoenzyme by these compounds” (para. 0051, last sentence). Thus, the disclosure itself establishes that wild-type IDH1 inhibition does not necessarily produce a therapeutic effect in every disease or biological environment. This is consistent with the teachings of Winter (see “2. State of the prior art” subsection above).
Accordingly, practicing the claimed method for any disease or disorder would require a POSITA to determine, at a minimum:
whether wild-type IDH1 contributes to the pathogenesis or survival of the affected cells;
note: such a study is not routine optimization, but rather requires independent biological investigation into the disease mechanism itself;
whether the relevant tissue exhibits glucose, magnesium, or other metabolic conditions that permit effective inhibition;
which claimed compound (out of the extremely broad genus) is active under those conditions; and
what dose and treatment regimen would be effective in the patient.
The specification provides no generally applicable guidance or predictive relationship by which these determinations may be made across the unrestricted range of diseases and disorders encompassed by the claim.
The required experimentation is further compounded by the breadth of the claimed compound genus. The claims encompass numerous independently variable structural groups, including broadly defined substituted alkyl, substituted aryl, substituted heteroaryl, and other substituted groups, without meaningfully limiting the identity, number, or position of the permitted substituents. The specification does not provide a structure-activity relationship or other predictive guidance identifying which combinations of substituents would retain wild-type IDH1 inhibitory activity, remain effective under the required metabolic conditions, and produce a therapeutic effect in any disease or disorder.
In view of the extreme breadth of both the claimed disease genus and compound genus, the limited scope of the working examples, the absence of predictive guidance or meaningful structure-activity relationships, and the context-dependent and unpredictable nature of wild-type IDH1 inhibition, practicing the full scope of the claimed method would require undue experimentation amounting to a research program rather than routine verification. The specification, therefore, does not enable the full scope of the instant claims without undue experimentation.
Claims 2-4, 7, 10, 13, 16, 18, 19, 26, 31, 34, 43, 53-55, 61, and 74, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Written Description
Claims 1-4, 7, 10, 13, 16, 18, 19, 26, 31, 34, 43, 53-55, 61, and 74 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims
See “4. The breadth of the claims” subsection of the “Scope of Enablement” section above.
The presence or absence of working examples
See “5. The presence or absence of working examples” subsection of the “Scope of Enablement” section above.
State of the prior art
See “2. State of the prior art” subsection of the “Scope of Enablement” section above.
The instant specification does not demonstrate that the inventor(s), at the time the application was filed, had possession of the claimed invention
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).
In the instant case, the specification only provides 30 specific examples of compounds, all of which are confined to a very narrow subgenus. Recall, all 30 examples have:
R1 = pyrrolyl, pyrazolyl, thiophenyl, or methyl-substituted version of any of these groups,
R2 = R2’ = Me,
R3 = -CH2-phenyl (wherein the phenyl is substituted with F or CF3),
X1 = NH,
A1 = phenyldiyl, oxazoldiyl, or thiazoldiyl,
L1 = covalent bond, -NHC(O)-, -C(O)NH-, or -C(O)O-,
R4 =
C1-C6 alkyl optionally substituted with OH or halo,
Unsubstituted C2-6 alkenyl,
Unsubstituted C2-6 alkynyl,
Halo,
Unsubstituted C1-6 alkoxy,
H, or
Unsubstituted C3-6 cycloalkyl
OR
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is
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or
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.
The variables listed above encompass a much narrower genus of compounds compared to the genus currently recited in instant claim 1. According to the MPEP, a very narrow subgenus of compounds does not adequately reflect a claimed genus that is structurally diverse. In the instant case, the instant claims are extremely broad as explained in “4. The breadth of the claims” subsection of the “Scope of Enablement” section above.
Accordingly, the disclosed species do not adequately reflect the structural diversity of the claimed genus and do not demonstrate possession of the full scope of compounds recited in instant claims 1-4, 7, 10, 13, 16, 18, 19, 26, 31, 34, 43, 53-55, 61, and 74.
The instant specification also fails to demonstrate possession of the full scope of the claimed therapeutic methods. The claim encompasses treatment of any disease or disorder in a patient by administering the claimed compounds, yet the instant specification only provides experimental support for pancreatic, colorectal, and lung cancer (para. 0046, 0048, and 0049).
Moreover, the specification expressly teaches that the therapeutic activity of wild-type IDH1 inhibition is not generally applicable, but instead depends on specific biological conditions. Specifically, the specification states:
“This observation is based on the scientific discovery that these drugs become potent inhibitors of the wild-type IDH1 isoenzyme in cancer cells, but only under specific conditions present in tumors: low glucose when wtIDH1 is critical for PC cell survival and low magnesium which is required for effective allosteric inhibition of the wtIDH1 isoenzyme by these compounds” (para. 0051, last sentence).
Thus, the specification itself recognizes that successful therapeutic inhibition of wild-type IDH1 is dependent upon the particular metabolic environment and disease context, rather than being generally applicable to all diseases or disorders. Note: This teaching from the instant specification is consistent with the teachings of Winter (see “2. State of the prior art” subsection in the “Scope of Enablement” section above).
Accordingly, the disclosure does not reasonably convey possession of a method for treating the full claimed genus of “a disease or disorder.” The instant specification does not provide any generally applicable guidance, predictive basis, or representative examples from which a POSITA could reasonably conclude that the demonstrated therapeutic efficacy in pancreatic, colorectal, and lung cancer would extend to the full range of diseases and disorders encompassed by the claims. Therefore, the written description is not commensurate with the broad scope of the claimed therapeutic methods.
Claim 74, which is dependent on claim 1, are also rejected for further requiring and/or reciting elements that do not have written description support.
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.
Claims 1-4, 7, 10, 13, 16, 18, 19, 26, 31, 34, 43, 53-55, 61, and 74 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.
Claims 1-4, 7, 10, 13, 31, 34, and 43 recite “substituted” without specifying what substituents are encompassed. The specification does disclose specific types of substituents encompassed by the modifier, “substituted:”
“When a chemical group is used with the ‘substituted’ modifier, one or more hydrogen atom has been replaced, independently at each instance, by —OH, —F, —Cl, —Br, —I, —NH2, —NO2, —CO2H, —CO2CH3, —CO2CH2CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —NHCH3, —NHCH2CH3, —N(CH3)2, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, —OC(O)CH3, —NHC(O)CH3, —S(O)2OH, or —S(O)2NH2” (see para. 00187, 1st sentence).
However, the instant compounds include substituents outside the stated definition. For example, instant compound IAP-1-39 (see pg. 57 of instant specification and 3rd to last compound of instant claim 53; recall, instant claim 53 is dependent on claim 1), has the following structure:
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wherein R1 is a pyrrolyl ring substituted with a methyl group (i.e., R1 is a substituted heteroaryl). However, an alkyl group is not included in the above list of substituents encompassed by the modifier, “substituted.” Therefore, Examiner interprets the disclosed definition of “substituted” as not exhaustive, and the claims are reasonably interpreted as encompassing additional, unspecified substituents. This substantially expands the scope of the claimed compound genus beyond the substituents expressly described in the specification within the 1st sentence of para. 00187 (which is also listed in the previous paragraph).
Therefore, it is unclear what chemical structures are encompassed by the term “optionally substituted” as the term could include an unlimited range of functional groups and substitution patterns, including those that would significantly alter the chemical and physical properties of the claimed compound. As such, a POSITA would not be able to determine the metes and bounds of the claimed invention with reasonable certainty and claim 1 is rendered indefinite.
Claims 16, 18, 19, 26, 53-55, 61, and 74, which are dependent on claim 1, are also rejected for further requiring and/or reciting the indefinite limitation of claim 1.
Claim Rejections - 35 USC § 112(d)
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 3 and 53 are 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.
Claim 3 recites, “L2 and L3 is… -NRaC(O)-, -C(O)NRa-, …”
Claim 3 is dependent on claim 1 which recites, “L2 and L3 is… -NRaC(O)-, -NRaC(O)-, …”
Claim 1 does not state that L2 and L3 could be -C(O)NRa-
Therefore, claim 3 fails to further limit the subject matter of the claim upon which it depends.
Claim 53 is dependent on claim 1 and recites the following compound:
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wherein L2 = -C(O)NH-
However, L2 = -C(O)NH- is not an option in claim 1. Therefore, claim 53 fails to further limit the subject matter of the claim upon which it depends.
Claim 53 further recites the following compound:
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wherein L2 is absent and L3 is -C(O)NH-
However, L2 = absent and L3 = -C(O)NH- is not an option in claim 1. Therefore, claim 53 fails to further limit the subject matter of the claim upon which it depends
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, 2, 4, 7, 10, 16, 26, 31, 34, 55, and 61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Okoye-Okafor et al. (Okoye-Okafor) (Okoye-Okafor, U. C. et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nature Chemical Biology 2015, 11, 878-886.)
Okoye-Okafor discloses the following compound (see Supplementary Table 2; herein, referred to as GSK864):
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. GSK864 is a compound of the instant claims wherein:
R1 = C4 heteroaryl (i.e., pyrrolyl),
R2 = substituted C1 alkyl (i.e., C1 alkyl substituted with NH2 and oxo),
R2’ = C1 alkyl,
R3 = substituted aralkyl (i.e., -CH2-phenyl, wherein the phenyl is substituted with F),
X1 = NH,
A1 = substituted arenediyl (i.e., phenyl substituted with 2 Me), L1 = covalent bond, and R4 = C1 alkoxy OR
A1 = substituted arenediyl (i.e., phenyl substituted with 2 Me and 1 OMe), L1 = covalent bond, and R4 = H OR
A1 = substituted arenediyl (i.e., phenyl substituted with 1 Me and 1 OMe), L1 = covalent bond, and R4 = Me.
Therefore, GSK864 anticipates instant claims 1, 2, 4, 7, 10, 16, 26, 31, and 34.
Pharmacokinetic analysis studies in mice were also conducted. “Mice received GSK864 (213 mg/kg, 10 mL/kg) via intraperitoneal (i.p.) administration. The i.p. formulation was PG:DMSO:PEG400:H2O (16.7:3.3:40:40) and was prepared by the Pharmaceutical Development group (GSK)” (3rd page after pg. 886, left col., “Pharmacokinetic analysis in mouse” section). In other words, Okoye-Okafor discloses a pharmaceutical composition comprising a compound of instant claim 1 and an excipient. This pharmaceutical composition anticipates instant claim 55.
Okoye-Okafor also discloses that GSK864 can reduce leukemic blasts in mice (see pg. 883-884, “GSK864 reduces leukemic blasts in vivo” section). Therefore, Okoye-Okafor demonstrates a method of treating leukemia in mice comprising administering to the mice an effective amount of a compound of instant claim 1. In other words, Okoye-Okafor also anticipates instant claim 61.
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, 10, 13, 16, 19, 26, 31, 34, 53, 55, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over:
Zhang et al. (Zhang) (WO2018071404A1; published April 19, 2018) and
Okoye-Okafor et al. (Okoye-Okafor) (Okoye-Okafor, U. C. et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nature Chemical Biology 2015, 11, 878-886.) in view of
Lowe (Lowe, D. More magic Methyls, Please. Science: In the Pipeline 2013.)
Zhang and Okoye-Okafor disclose compounds that are very similar to compounds encompassed by the instant claims (see below for a comparison; the differences between the structures are circled for clarity):
Office Action Table 1
Compound disclosed by Zhang or Okoye-Okafor
Compound encompassed by instant claims
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(Zhang refers to this compound as ISO-2-25; see pg. 30).
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This species is a compound encompassed by instant claims 1-4, 7, 10, 19, and 34, wherein:
R1 = C4 heteroaryl (i.e., pyrrolyl),
R2 = R2’ = C1 alkyl,
R3 = substituted aralkyl (i.e., -CH2-phenyl, wherein the phenyl is substituted with F),
X1 = NH,
A1 = arenediyl (i.e., phenyl),
L1 = -NRbC(O)- (wherein Rb = H), and
R4 = C2 alkenyl.
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(Zhang refers to this compound as ISO-2-19; see pg. 30).
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446
604
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This species is a compound encompassed by instant claims 1-4, 7, 13, 19, and 34, wherein:
R1 = C4 heteroaryl (i.e., pyrrolyl),
R2 = R2’ = C1 alkyl,
R3 = substituted aralkyl (i.e., -CH2-phenyl, wherein the phenyl is substituted with F),
X1 = NH,
A1 = heteroarenediyl (i.e., thiophenyl),
L1 = -NRbC(O)- (wherein Rb = H), and
R4 = C2 alkenyl.
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450
577
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(Zhang refers to this compound as ISO-2-30-R; see pg. 31).
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448
570
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This species is a compound encompassed by instant claims 1-4, 7, 10, 16, and 31, wherein:
R1 = C4 heteroaryl (i.e., pyrrolyl),
R2 = R2’ = C1 alkyl,
R3 = substituted aralkyl (i.e., -CH2-phenyl, wherein the phenyl is substituted with F),
X1 = NH,
A1 = substituted arenediyl (i.e., phenyl substituted with -NHC(O)(C2 alkenyl)),
L1 = covalent bond, and
R4 = C1 alkoxy.
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385
507
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(Okoye-Okafor refers to this compound as GSK321; see pg. 879, Figure 1a)
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387
503
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This species is the enantiomer of the 1st compound recited in instant claim 53 and a compound encompassed by instant claims 1-4, 7, 10, 16, and 26, wherein:
R1 = C4 heteroaryl (i.e., pyrrolyl),
R2 = R2’ = C1 alkyl,
R3 = substituted aralkyl (i.e., -CH2-phenyl, wherein the phenyl is substituted with F),
X1 = NH,
A1 = substituted arenediyl (i.e., phenyl substituted with -CHOH-CH3),
L1 = covalent bond, and
R4 = H.
Thus, the main structural difference between the compounds disclosed by Zhang or Okoye-Okafor and the corresponding species encompassed by the instant claims is the presence of an additional methyl group at the identified position of the fused-ring core in the instant compounds.
Zhang and Okoye-Okafor disclose the closely related compounds as being inhibitors of mutated IDH1 proteins (see abstract of Zhang and Okoye-Okafor). Accordingly, a POSITA seeking additional compounds having the same utility as the compounds of Zhang and Okoye-Okafor would have regarded the compounds of the prior art as suitable lead compounds for further structural modification.
Neither Zhang nor Okoye-Okafor explain the importance of an additional methyl group being incorporated in a medicinal compound. Lowe is relied upon for this disclosure.
Lowe teaches that “[m]edicinal chemists have long been familiar with the ‘magic methyl’ effect. That’s the dramatic change in affinity that can be seen (sometimes) with the addition of a single methyl group in just the right place” (1st two sentences of article). Lowe provides some examples of how the incorporation of an additional methyl group in a medicinal compound could significantly alter the potency of the drug (two of those examples are reproduced below):
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180
532
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152
538
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.
In view of Lowe, one of ordinary skill in the art would have been motivated to prepare methyl-substituted analogs of the compounds disclosed by Zhang and Okoye-Okafor in order to evaluate whether methyl substitution altered or improved the compound’s potency. A POSITA would have understood that methyl substitution may affect other compound properties such as solubility (which may affect bioavailability), molecular conformation, binding interactions, and how the compound is metabolized (P. Zhang, Demystifying the Magic Methyl Effect. MacMillan Group Meeting, 2015.; see slide 7). As such, a POSITA would have regarded methylating a compound as a recognized lead-optimization strategy.
Moreover, the prior art compounds present a finite number of available positions at which an additional methyl substituent could be introduced while retaining the remainder of the disclosed molecular structure. These positions represent a limited number identified structural modifications that could have been routinely prepared and evaluated by a POSITA. A POSITA would have found it obvious to try and prepare, then test the corresponding methyl-substituted analogs using routine organic chemistry synthesis and in vitro/ in vivo experimentation, with a reasonable expectation that at least some of the resulting analogs (including the compounds on the right-hand side of Office Action Table 1) would retain the biological activity of the closely related compounds disclosed by Zhang and Okoye-Okafor and would be useful for the same disclosed purpose. See MPEP §2143 > I. Examples of Rationales > (E) Obvious to try.
Accordingly, 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 compounds disclosed by Zhang and Okoye-Okafor by introducing a methyl group at any available positions (including the position recited in the instant claims), and to test the resulting analogs for IDH1 inhibitory activity. Selection of the presently claimed methyl-substituted species from this limited number of closely related analogs would have amounted to routine optimization of a known lead compound.
Therefore, instant claims 1-4, 7, 10, 13, 16, 19, 26, 31, 34, and 53 are rendered obvious.
Furthermore, Zhang and Okoye-Okafor disclose that the prior art compounds are inhibitors of IDH1 (see abstract of both prior art). Since the presently claimed compounds are obvious methyl-substituted analogs of those known IDH1 inhibitors for the reasons discussed above, one of ordinary skill in the art would likewise have found it obvious to formulate the modified compounds into pharmaceutical compositions (such as the aqueous solution described in Okoye-Okafor; see 3rd page after pg. 886, left col., “Pharmacokinetic analysis in mouse” section) and administer them for the same therapeutic purpose taught by Zhang and Okoye-Okafor with a reasonable expectation of success.
Therefore, instant claims 55, and 61 are 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
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