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, 2, 5, 9, 11-13, 15, 25, 27, 32, 51-53, 56, 69, 70, 73, 75, and 81 are pending. Claims 3, 4, 6-8, 10, 14, 16-24, 26, 28-31, 33-50, 54, 55, 57-68, 71, 72, 74, 76-80, and 82-85 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2022/081432, filed on December 13, 2022. This application also claims the benefits of U.S. Provisional Application No. 63/288,945, filed on December 13, 2021.
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).
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.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet preferably within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, "The disclosure concerns," "The disclosure defined by this invention," "The disclosure describes," etc. In addition, the form and legal phraseology often used in patent claims, such as "means" and "said," should be avoided.
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
Claim 2 is objected to because of the following informalities:
For consistency, in claim 2:
“pharmaceutically salt thereof” should read “pharmaceutically acceptable salt thereof”
Appropriate correction is required.
Claim 52 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 51. Claim 51 is dependent on claim 2 and recites the limitation, “wherein B is a monovalent form of asciminib or a monovalent form of GNF-2.” Claim 52 is also dependent on claim 2 and recites the limitation, “wherein B is a monovalent form of
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.” The two structures recited in claim 52 are the structures of asciminib and GNF-2, respectively. Therefore, claim 52 is a substantial duplicate of claim 51.
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).
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, 2, 5, 9, 11-13, 15, 25, 27, 32, 51-53, 69, 70, 73, 75, and 81 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:
A – L1 – B; or a pharmaceutically acceptable salt thereof, wherein
A is a monovalent form of an ABL ATP binding site inhibitor selected from the group consisting of:
dasatinib, ponatinib, imatinib, nilotinib, bosutinib, bafetinib, olverembatinib, tozasertib, PF-114, rebastinib, danusertib, HG-7-85-01, and
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;
L1 is a divalent linker as recited in instant claims 9, 15, and 27; and
B is a monovalent form of an ABL myristoyl binding site inhibitor selected from the group consisting of asciminib and GNF-2;
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of point (1) above, or a pharmaceutically acceptable salt thereof;
A method of treating leukemia in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of point (1) above, or a pharmaceutically acceptable salt thereof;
A method of treating Alzheimer’s disease or Parkinson’s disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of point (1) above, or a pharmaceutically acceptable salt 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:
bivalent compounds that are ABL inhibitors comprising an ABL ATP binding site inhibitor moiety and an ABL myristoyl binding site inhibitor moiety and
uses thereof.
State of the prior art and the predictability or lack thereof in the art
Prior art referenced:
Johnson et al. (Johnson) (Johnson, T. K. et al. Synergy and Antagonism between Allosteric and Active-Site Inhibitors of Abl Tyrosine Kinase. Angew. Chem. Int. Ed. 2021, 60, 20196-20199.)
The prior art teaches that the relationship between ABL ATP binding site inhibitors and ABL myristoyl binding site inhibitors is unpredictable and dependent on the particular combination of inhibitors selected.
For example, Johnson teaches “that synergy between ATP-competitive and allosteric inhibitors of Abl requires a “match” of kinase conformation. In biochemical and cellular assays, GNF-2 and asciminib were synergistic only with inhibitors that stabilize the closed conformation of Abl” (paragraph before “Acknowledgements”).
Furthermore, Johnson “observed antagonism (CI>1) between allosteric and ATP-competitive inhibitors of Abl” for 8 specific combinations (see pg. 20197, left col., 1st sentence). The results are summarized in Table 1 below:
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.
Therefore, Johnson demonstrates that simultaneous inhibition of the ATP binding site and myristoyl binding site does not inherently result in synergistic or added ABL inhibition. Rather, the biological effect depends on the specific structural properties of the ATP-site inhibitor, the myristoyl-site inhibitor, and their resulting effects on ABL kinase conformation.
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 a monovalent ABL ATP binding site inhibitor covalently bound to a monovalent ABL myristoyl binding site inhibitor. The claimed genus encompasses a large number of structurally diverse compounds because the claims do not limit the chemical structure of ABL ATP binding site inhibitor and/or the ABL myristoyl binding site inhibitor.
Furthermore, the claims do not require any particular site of attachment between the two binding moieties. Thus, the claimed genus also encompasses compounds wherein the A-moiety and the B-moiety are covalently attached through any chemically permissible position on either binding moiety.
Additionally, the claims encompass both direct covalent attachment of the A and B moieties as well as the attachment of the two moieties via a linker wherein the linker is not limited by chemical structure, length, rigidity, hydrophobicity, hydrophilicity, or other structural properties. Accordingly, the claims encompass a vast genus of compounds having substantial structural variability in the A-moiety, B-moiety, and linker.
The method claims are also broad insofar as they encompass treatment of a wide range of diseases, including any cancer, any neurodegenerative diseases, and any ABL-associated diseases. The claimed method of treating cancer is not limited to cancers known to be driven by ABL kinase activity, but instead encompasses all cancers which includes those having diverse and unrelated pathological mechanisms. Similarly, the claimed method of treating neurodegenerative diseases encompass a broad class of diseases having different pathological mechanisms, including diseases that are not established as being dependent upon ABL kinase activity.
The presence or absence of working examples
The instant specification only provides 13 specific examples of compounds encompassed by instant claim 1 (see instant specification, pg. 136, lines 25-27) which include:
DasatiLink-1, DasatiLink-2, DasatiLink-3, DasatiLink-4, (see Fig. 13B)
PonatiLink-1-12, PonatiLink-1-16, PonatiLink-1-20, PonatiLink-1-24, PonatiLink-1-28, (see Fig. 19), and
PonatiLink-2-7-4, PonatiLink-2-7-6, PonatiLink-2-7-8, PonatiLink-2-7-10 (see Fig. 20).
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). For example, according to instant claims 1 and 2, the A-moiety and B-moiety can be any ABL ATP binding site inhibitor and any ABL myristoyl binding site inhibitor, respectively. However, in the instant case, the A-moiety used in the specific examples is consistently either dasatinib or ponatinib and the B-moiety used is consistently asciminib (see instant claim 56 for structures), while the linker is consistently only variations of those recited in instant claims 9, 15, and 27. Accordingly, significant portions of the claimed structural space remain unexplored by the working examples. The examples, therefore, provide only limited information regarding how variations in the A-moiety and the linker structure/length affect ABL inhibitory activity (see Fig. 13B and Fig. 18 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 that selected compounds reduce cell viability of K562 leukemia cells (see Fig. 17 and 19-21) and inhibit ABL kinase activity (see Figs. 13B and 18). However, the instant specification does not provide working examples demonstrating therapeutic activity in other cancer types, other neurodegenerative disease models, or the full scope of ABL-associated diseases 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
Although the specification provides synthetic procedures for the 13 specific examples, it provides limited direction and guidance regarding which structural features of ABL inhibitors (that are not explicitly listed in the instant specification or are not currently known to be ABL inhibitors) are responsible for ABL inhibitory activity and how modifications to the ABL inhibitors and linker structure affect such activity. In the instant case, the A-moiety used in the specific examples is consistently either dasatinib or ponatinib and the B-moiety used is consistently asciminib, while the linker is consistently only variations of those recited in instant claims 9, 15, and 27. The specification does not provide guidance regarding the effect of modifying:
the linker structure and/or
the A-and B-moiety of a compound of instant claim 1 to an ABL binding site inhibitor that is not dasatinib/ponatinib or asciminib
in ABL1 inhibitory activity. The instant specification also does not provide a structure-activity relationship that would allow a POSITA to predict which structural features of a compound of instant claim 1 would retain or improve ABL1 inhibitory activity of the compound.
Because the claims encompass numerous variables, the required experimentation would involve not merely routine verification of activity but extensive exploration of the claimed genus to identify operative species which involves undue experimentation. Although a POSITA possesses expertise in medicinal chemistry and organic synthesis, such expertise cannot substitute for the absence of guidance in the specification. The issue is not whether a POSITA is capable of synthesizing and testing compounds encompassed by the claims. Rather, the issue is that the specification provides insufficient information to identify which structural modifications (e.g., which combinations of A-moiety, B-moiety, and linker) preserve or improve ABL inhibitory activity and which modifications destroy such activity. Consequently, a POSITA would be required to undertake a substantial medicinal chemistry research program to establish the relevant structure-activity relationships before the full scope of the claimed genus could be practiced.
The instant specification also provides insufficient direction and guidance regarding the full scope of the claimed therapeutic methods. The working examples demonstrate reduced viability of K562 leukemia cells and inhibition of ABL kinase activity by selected compounds. However, the specification does not provide sufficient guidance demonstrating how these results can be extrapolated to the full scope of claimed methods including the treatment of any cancer, any neurodegenerative disease, and any ABL-associated disease by any of the compounds within the broadly claimed genus.
The reduction of cell viability in a specific cancer cell line does not establish that the claimed genus of compounds would provide therapeutic benefit across all cancers having different genetic drivers and mechanisms of disease progression. Likewise, the demonstration of ABL kinase inhibition for selected compounds does not establish that all ABL-associated diseases would be responsive to treatment with the claimed compounds, especially in view of the teachings disclosed by Johnson.
Specifically, Johnson demonstrates that ABL inhibition is context-dependent and that productive inhibition of ABL through simultaneous ATP-site and myristoyl-site targeting requires conformational compatibility between the inhibitors. Therefore, even among diseases associated with ABL activity, a POSITA could not predict that every compound encompassed by the claimed genus would provide sufficient ABL modulation to achieve therapeutic benefit.
Therefore, practicing the full scope of the instant compound and method claims extends beyond routine optimization and would require a substantial medicinal chemistry research program to identify operative species within the claimed genus, thereby amounting to undue experimentation.
Written Description
Claims 1, 2, 5, 9, 11-13, 15, 25, 27, 32, 51-53, 69, 70, 73, 75, and 81 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 and the predictability or lack thereof in the art
See “2. State of the prior art and the predictability or lack thereof in the 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 13 specific examples of compounds, all of which are confined to a very narrow subgenus. Recall, all 13 examples have the same B-moiety; A-moiety is either ponatinib or dasatinib; and the linker is a slight variation of the linkers recited in instant claims 9, 15, and 27). 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, 2, 5, 9, 11-13, 15, 25, 27, 32, 51-53, 69, 70, 73, 75, and 81.
The instant specification also fails to demonstrate possession of the full scope of the claimed therapeutic methods.
The instant specification demonstrates that selected DasatiLink and PonatiLink compounds decrease cell viability of K562 leukemia cells and inhibit ABL kinase activity. However, K562 cells represent one specific cancerous cell line and do not adequately represent the broad genus of diseases encompassed by instant claims 70, 73, and 75.
The claimed methods encompass treatment of broad disease classes, including cancers, neurodegenerative diseases, and general ABL-associated diseases. These disease classes encompass diseases having diverse pathological mechanisms. Furthermore, the instant specification does not provide representative examples demonstrating treatment of different cancer types, neurodegenerative disease models, or the variety of diseases encompassed by the term “ABL-associated disease.”
Furthermore, demonstration that selected compounds (belonging to a very narrow subgenus) inhibit ABL kinase activity does not demonstrate possession of methods of treating every disease associated with ABL activity by administering to a subject in need thereof any compound encompassed by instant claim 1, especially in view of the teachings disclosed by Johnson.
Specifically, Johnson demonstrates that ABL inhibition is context-dependent and that productive inhibition of ABL through simultaneous ATP-site and myristoyl-site targeting requires conformational compatibility between the inhibitors. Therefore, even among diseases associated with ABL activity, a POSITA could not predict that every compound encompassed by the claimed genus would provide sufficient ABL modulation to achieve therapeutic benefit.
Accordingly, the disclosure of activity in a single leukemia cell model does not adequately represent the full therapeutic breadth of the claimed methods. Therefore, the specification does not reasonably convey that Applicant was in possession of methods of treating the full scope of cancers, neurodegenerative diseases, and ABL-associated diseases encompassed by the claims.
The instant specification provides adequate written description for the enabled elements [i.e., points (1) through (4)] as listed in the “Scope of Enablement” section above.
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, 5, 12, 25, 51-53, and 69 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Foreman et al. (Foreman) (WO2015106294A1; published July 16, 2015)
Foreman discloses compounds capable of modulating two or more binding sites on a protein such as Bcr-ABL tyrosine kinase (abstract). Specifically, “[i]n one embodiment, a bivalent compound may include a first pharmacophore that may bind to the myristoyl binding pocket of Bcr-Abl tyrosine kinase and a second pharmacophore that may bind to the ATP binding pocket of Bcr-Abl tyrosine kinase” (para. 0015).
One of the bivalent compounds disclosed by Foreman is the following:
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(see pg. 76, Example 4; herein, referred to as Foreman-Example-4).
Foreman-Example-4 anticipates instant claims 1, 2, 5, 12, 25, and 51-53 as indicated below:
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wherein:
A = a monovalent form of the following:
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(i.e., an ABL ATP binding site inhibitor, as disclosed in instant claim 12, that is outlined with a solid box),
B = a monovalent form of GNF-2 (i.e., an ABL myristoyl binding site inhibitor that is outlined with a dashed box),
Linker = -L101-L102-L103-L104-L105- wherein:
L101 = unsubstituted heteroalkylene
L102 = -C(O)-
L103 = substituted arylene
L104 = -C(O)-
L105 = unsubstituted heteroalkylene.
To obtain the 1H NMR spectrum of Foreman-Example-4, the compound was first dissolved in DMSO-d6 (see Foreman, pg. 76, lines 13-14). Note: DMSO is known to be an excipient in pharmaceutical compositions (see 1st sentence of the following article: McKim et al. Dimethyl Sulfoxide USP, PhEur in Approved Pharmaceutical Products and Medical Devices. Pharmaceutical Technology. 2008, 32.).
Therefore, Foreman-Example-4 dissolved in DMSO anticipates instant claim 69.
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.
Rejection Part 1:
Claims 1, 2, 5, 11-13, 32, 51-53, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over:
Foreman et al. (Foreman) (WO2015106294A1; published July 16, 2015)
As stated above in the “Claim Rejections - 35 USC § 102” section, Foreman-Example-4 has the following structure:
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and anticipates instant claims 1, 2, 5, 12, 25, and 51-53.
Foreman does not explicitly disclose bivalent compounds wherein the ABL ATP binding site inhibitor (i.e., corresponds to A-moiety in the instant application) is any one of the following:
imatinib, nilotinib, bosutinib, ponatinib, or bafetinib.
However, Foreman does state:
“In certain embodiments, a Bcr-Abl tyrosine kinase ATP binding site ligand may be represented by imatinib, nilotinib, bosutinib, ponatinib, DCC-2036, GNF5, or bafetinib” (para. 0021).
Therefore, a person of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to modify Foreman-Example-4 by substituting the A-moiety with imatinib, nilotinib, bosutinib, ponatinib, or bafetinib. A POSITA would have been motivated to make such a modification because Foreman expressly identifies imatinib, nilotinib, bosutinib, ponatinib, or bafetinib as a suitable BCR-ABL tyrosine kinase ATP binding site inhibitor for use as the A-moiety. Furthermore, because Foreman provides a limited number of specifically identified ABL ATP binding site inhibitors, a POSITA would have had a reasonable expectation of success in selecting imatinib, nilotinib, bosutinib, ponatinib, or bafetinib from among the disclosed alternatives to obtain a bivalent compound capable of targeting BCR-ABL.
Thus, instant claims 1, 2, 5, 11-13, 32, and 51-53 are rendered obvious.
After synthesizing the modified compound, to obtain the 1H NMR spectrum of the compound, it would be necessary to dissolve the compound in a solvent like DMSO-d6 (see Foreman, pg. 76, lines 13-14, for example). Note: DMSO is known to be an excipient in pharmaceutical compositions (see 1st sentence of the following article: McKim et al. Dimethyl Sulfoxide USP, PhEur in Approved Pharmaceutical Products and Medical Devices. Pharmaceutical Technology. 2008, 32.). Thus, a composition comprising the modified compound and an excipient like DMSO would read on instant claim 69. Hence, instant claim 69 would also be rendered obvious.
Rejection Part 2:
Claims 1, 2, 5, 12, 25, 51-53, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over:
Foreman et al. (Foreman) (WO2015106294A1; published July 16, 2015)
As stated above in the “Claim Rejections - 35 USC § 102” section, Foreman-Example-4 has the following structure:
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and anticipates instant claims 1, 2, 5, 12, 25, and 51-53.
Foreman does not explicitly disclose bivalent compounds wherein the ABL myristoyl binding site inhibitor (i.e., corresponds to B-moiety in the instant application) is asciminib.
However, Foreman does state:
“For example, a Bcr-Abl tyrosine kinase ligand may be represented by:
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” (para. 0025). Note: this structure provided in para. 0025 of Foreman is the structure of asciminib.
Therefore, a person of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to modify Foreman-Example-4 by substituting the B-moiety with asciminib. A POSITA would have been motivated to make such a modification because Foreman expressly identifies asciminib as a suitable BCR-ABL tyrosine kinase myristoyl inhibitor for use as the B-moiety.
Thus, instant claims 1, 2, 5, 12, 25, and 51-53 are rendered obvious.
After synthesizing the modified compound, to obtain the 1H NMR spectrum of the compound, it would be necessary to dissolve the compound in a solvent like DMSO-d6 (see Foreman, pg. 76, lines 13-14, for example). Note: DMSO is known to be an excipient in pharmaceutical compositions (see 1st sentence of the following article: McKim et al. Dimethyl Sulfoxide USP, PhEur in Approved Pharmaceutical Products and Medical Devices. Pharmaceutical Technology. 2008, 32.). Thus, a composition comprising the modified compound and an excipient like DMSO would read on instant claim 69. Hence, instant claim 69 would also be rendered obvious.
Rejection Part 3:
Claims 1, 2, 5, 11-13, 32, 51-53, 70, 75, and 81 are rejected under 35 U.S.C. 103 as being unpatentable over:
Foreman et al. (Foreman) (WO2015106294A1; published July 16, 2015)
As explained in “Rejection Part 1” of this section, the modified compound (which is Foreman-Example-4 wherein the A-moiety is replaced with any one of the following ABL ATP binding site inhibitors: imatinib, nilotinib, bosutinib, ponatinib, or bafetinib) reads on instant claims 1, 2, 5, 11-13, 32, and 51-53. This modified compound is also encompassed by the formula disclosed in Foreman, para. 0005.
Foreman further teaches:
“In another aspect, a method of treating a disease associated with Bcr-Abl tyrosine kinase in a patient in need thereof is provided. The method comprises administering to the patient the bivalent compound as described [in para. 0005]” (see para. 0006).
According to Foreman, a disease associated with Bcr-Abl tyrosine kinase includes cancer (para. 0088). Foreman further demonstrates that representative bivalent compounds (encompassed by the formula recited in para. 0005) can inhibit Abl kinase activity (see Example 9).
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 use the modified compound in:
A method of treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the modified compound;
A method of treating an ABL-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of the modified compound; and
A method of reducing the level of activity of ABL in a cell, said method comprising contacting the cell with an effective amount of the modified compound;
A POSITA would have been motivated to use the modified compound for the instantly claimed methods because Foreman expressly teaches that the disclosed genus of bivalent compounds (see Foreman, para. 0005), which encompass the modified compound, is useful for treating diseases associated with Bcr-Abl tyrosine kinase, including cancer. Furthermore, Foreman demonstrates that representative compounds within the disclosed genus inhibit Abl kinase activity, thereby providing a reasonably expectation that structurally related bivalent compounds within the same disclosed genus, including the modified compound, would similarly inhibit Abl activity and be useful for treating Abl-associated diseases, including cancer, and reducing the activity of Abl in a cell.
Rejection Part 4:
Claim 73 is rejected under 35 U.S.C. 103 as being unpatentable over:
Foreman et al. (Foreman) (WO2015106294A1; published July 16, 2015) in view of
Schlatterer et al. (Schlatterer) (Schlatterer, S. D. et al. c-Abl in Neurodegenerative Disease. J Mol Neurosci 2011, 45, 445-452),
Foreman discloses compounds capable of modulating two or more binding sites on a protein such as Bcr-ABL tyrosine kinase (abstract). Specifically, “[i]n one embodiment, a bivalent compound may include a first pharmacophore that may bind to the myristoyl binding pocket of Bcr-Abl tyrosine kinase and a second pharmacophore that may bind to the ATP binding pocket of Bcr-Abl tyrosine kinase” (para. 0015).
One of the bivalent compounds disclosed by Foreman is the following:
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(see pg. 65, Example 2; herein, referred to as Foreman-Example-2) and is also encompassed by instant claim 1 wherein the A-moiety is a monovalent form of dasatinib (i.e., an ABL ATP binding site inhibitor) and the B-moiety is a monovalent form of GNF-2 (i.e., an ABL myristoyl binding site inhibitor). Foreman-Example-2 was also shown to inhibit ABL1 kinase activity (see Foreman, Example 9).
Foreman does not explicitly disclose the relationship between ABL1 kinase activity and neurodegenerative diseases. Schlatterer is relied upon for this disclosure.
Schlatterer discloses that “activation of c-Abl [same as Abl1, see Schlatterer, pg. 445, right col., 1st sentence] in forebrain neurons in mice can cause neurodegeneration and neuroinflammation, indicating that c-Abl activation alone is sufficient to cause neurodegenerative pathology” and that “[t]hese studies taken together suggest that c-Abl is a provocative target for therapeutics for neurodegenerative disease” (pg. 450, left col., paragraph before “Acknowledgments,” 2nd and 3rd sentence).
Therefore, a person of ordinary skill in the art would have found it prima facie obvious before the effective filing date of the claimed invention to use Foreman-Example-2 in a method of treating a neurodegenerative disease in a subject in need thereof, wherein said method comprises administering a therapeutically effective amount of the compound of Foreman-Example-2 to said subject. A POSITA would have been motivated to use Foreman-Example-2 for treating a neurodegenerative disease in a subject in need thereof since Schlatterer teaches that activation of ABL1 kinase activity alone can cause neurodegeneration and identifies ABL1 kinase as a therapeutic target for neurodegenerative disease. Furthermore, Foreman demonstrates that Foreman-Example-2 inhibits ABL kinase activity. Therefore, a POSITA would have had a reasonable expectation that administering an ABL kinase inhibitor, such as Foreman-Example-2, would reduce ABL1 kinase activity and provide therapeutic benefit in neurodegenerative diseases associated with ABL1 activation.
Allowable Subject Matter
Claim 56 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form.
Conclusion
Claims 1, 2, 5, 9, 11-13, 15, 25, 27, 32, 51-53, 69, 70, 73, 75, and 81 are rejected. Claim 56 is objected to. 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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