DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-3, 5, 12, 14-26, 28, and 33 were previously pending. Claim 12 is amended, claims 14-26, 28, and 33 have been cancelled, and new claims 39-43 have been added.
Claims 1-3, 5, 12, and 39-43 are pending.
Priority
Instant application 18/795,000, filed 08/05/2024 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 12/19/2024 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 3, 5, and 12 in the reply filed on 08/31/2026 is acknowledged. New claims 39-43 are included in Group I. Group II, claims 14-26 and 33, was cancelled in the response filed 08/31/2026.
Applicant’s election without traverse of the species Example 12,
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is also acknowledged.
Examination will begin with the elected species. In accordance with MPEP 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched, and applicable prior art was identified. Therefore, the search has not been extended unnecessarily to encompass the entire scope of the compounds of Formula (I). See MPEP 803.02.
The elected species reads on claims 1-3, 12, and 39-43. Claim 5, which is drawn to a compound formula not reading on the elected species, is withdrawn from further consideration pursuant to 37 CFR 1.142(b), there being no allowable generic or linking claim.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 53, para. 0139 of the specification. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
Claims 40 and 42 recite an “effective amount” of a compound or pharmaceutical composition. The phrase “effective amount” is being interpreted in light of the specification to mean an amount that achieves a desired or observable therapeutic effect (page 47, para. 0112):
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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.
Claim 40 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.
The instant specification, while being enabling for treating certain types of cancer and fibrosis, does not reasonably provide enablement for treating all cancers and fibrotic diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to compounds of Formula (II), found in page 8 of the specification. The compounds are a class of transforming growth factor beta receptor 1 (TGFβR1, also known as ALK5) inhibitors.
Breadth of the claims:
The claims are broadly directed to the use of the compounds of Formula (II) for the treatment of all cancers or fibrotic diseases.
Level of ordinary skill in the art:
The artisans using applicant’s method would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
For example, different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
State of the prior art and predictability in the art:
With respect to TGFβR1 inhibition for treating cancer or fibrosis, HERBERTZ (“Clinical Development of Galunisertib (LY2157299 Monohydrate), a Small Molecule Inhibitor of Transforming Growth Factor-Beta Signaling Pathway.” Drug Design, Development and Therapy, vol. 9, Aug. 2015, pp. 4479–99) provides an overview of the prior art.
Herbertz is drawn to the development of the TGFβR1 inhibitor galunisertib which was until recently under clinical development. Herbertz also discloses other TGFβ inhibitors in clinical development and their indications (see pages 4482-83, Table 2). Additionally, Herbertz states that “Given the structural and genetic similarities of the different TGF-β signaling pathways, inhibitors must be highly specific to block the intended activation pathway…In contrast to the ALK1 inhibitors, the inhibition of the ALK5 pathway blocks activation of different intracellular proteins (e.g., SMAD2/3) and alters the vascular and smooth muscle cell compartment. This may improve delivery of chemotherapy although it may have a reduced inhibitory effect on pro-angiogenic factors, such as vascular endothelial growth factor and basic fibroblast growth factor. In contrast to ALK1 inhibitors, ALK5 inhibitors increase angiogenesis in cell cultures of normal endothelial cells.” (see page 4481, col. 2, para. 2).
Specific cancers and fibrotic diseases associated with the TGFβR1 signaling pathway and/or pSMAD2 under investigation for galunisertib are disclosed in Table 5 and pages 4491-4494. Herbertz does not disclose compounds having any structural similarity to the compounds of the instant claims.
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
That a single compound or class of compounds can be used to treat all cancers embraced by the claims is an incredible finding for which Applicant has not provided supporting evidence. Applicant has not provided competent evidence or disclosed tests that are highly predictive for the pharmaceutical use for treating all cancers and fibrotic diseases by administering the instant claimed compounds.
The specification does not show any examples where compounds of the claims were used to treat the full scope of cancers and fibrotic diseases as set forth in the claims, but merely demonstrates activity of certain compounds of Formula 1 as inhibitors of TGFβ (para. 00439) and demonstrates certain PK parameters of some example compounds in comparison to Galunisertib and LY3200882 (see para. 00441).
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
The amount of direction provided and working examples:
The only direction or guidance present in the instant specification is the disclosure of cancers applicant considers as treatable by the claimed compounds, and the activity of certain compounds of Formula 1 as inhibitors of TGFβ.
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine which particular cancer types out of all cancers recited would be benefited (treated) and would furthermore then have to determine which of the claimed compounds in the instant invention would provide treatment of the claimed diseases.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated by the compounds encompassed in the instant claims, with no assurance of success.
The rejection would be withdrawn if claim 40 was amended to incorporate the subject matter of claim 41 as follows:
A method to treat colon cancer, hepatocellular carcinoma (HCC), renal cancer, liver cancer, gastric cancer, or fibrosis in the liver or kidney, which comprises administering to a subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutical composition of claim 39.
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.
Claims 1-3, 12, and 39-43 are rejected under 35 U.S.C. 103 as being unpatentable over FINLAY (WO 2009022171 A1; cited in IDS).
Finlay discloses compounds of formula (IB) for the treatment of cancer (Finlay, page 17):
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Wherein the variables are defined on pages 21-22, and specify that R33 is selected from, inter alia, C1-6 alkyl, optionally substituted with R43, wherein R43 is selected from, inter alia, carboxy. Finlay also teaches pharmaceutical compositions at pages 86-86; and teaches inclusion of additional therapeutic agents at pages 90-93.
In particular, Finlay teaches the compound of Example 203 (3-{[4-(5,6-Dimethyl-2-pyridin-2-ylpyridin-3-yl)oxypyridin-2-yl]-amino}benzoic acid), having the structure (page 156):
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Finlay fails to disclose a compound anticipating the instant claims. The above compound differs from the elected species by the linker L1, which is a C2 alkyl linker. See the comparison below:
Instant elected species
FINLAY
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However, Finlay teaches that R33 is selected from, inter alia, C1-6 alkyl, optionally substituted with R43, wherein R43 is selected from, inter alia, carboxy (pages 21-22). Therefore, Finlay provides a teaching to prepare compounds having an alkyl linker attached to a carboxy group.
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (G), it would have been prima facie obvious to modify Finlay’s compound of Example 203 to insert an alkyl linker between the carboxyl moiety and benzene ring. Finlay explicitly contemplates a C1-6 alkyl linker (R33 in Finlay’s Formula IB). Finlay therefore provides a suggestion to prepare compounds having homologous alkyl chains linking the aryl ring to the carboxyl substituent.
Finlay’s compounds are disclosed as ALK5 (TGFβR1) inhibitors useful for the treatment of cancer (title, abstract). Therefore, compounds and compositions reading on instant claims 1-3, 12, and 39-43 and their utility for treating cancer would have been prima facie obvious before the effective filing date of the instant application. A skilled artisan would have been motivated to prepare analogs of Finlay’s compound disclosed above with a reasonable expectation of success in obtaining compounds with utility for treating cancer, which is the utility disclosed for the claimed compounds.
Conclusion
Claims 1-3, 12, and 39-43 are rejected. Claim 5 is withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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