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 .
DETAILED ACTION
The preliminary amendment filed 11/05/2025, cancelled claims 21-34 and 36-41.
Claims 1-20 and 35 are pending and examined on the merits herein.
Priority
This application claims the following priority:
PNG
media_image1.png
109
667
media_image1.png
Greyscale
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.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 depends from claim 2, wherein claim 2 recites a compound of Formula I:
PNG
media_image2.png
208
225
media_image2.png
Greyscale
.
However, the stereochemistry of many of the bonds of the compounds in claim 5 are outside the scope of the stereochemistry of bonds depicted in Formula I.
For example, see the first compound in claim 5, which depicts dash bonds where Formula I depicts wedge bonds:
PNG
media_image3.png
211
237
media_image3.png
Greyscale
.
Additionally, the final compound of claim 5 is missing a “F,” which is outside of the scope of instant Formula I:
PNG
media_image4.png
240
312
media_image4.png
Greyscale
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.
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 2-17 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.
-In claim 2, which depends from claim 1 and is a prodrug of the compound of claim 1, it is not clear why the stereochemistry of
PNG
media_image5.png
208
225
media_image5.png
Greyscale
in claim 2, is different from the stereochemistry of
PNG
media_image6.png
169
199
media_image6.png
Greyscale
in claim 1. It is not clear if a stereochemistry typo was made, or if the difference in stereochemistry means that compounds of Formula I at the arrowed bonds’ positions can have any type of spatial arrangement, or if these compounds must have the spatial arrangement depicted by the solid bonds of Formula I.
In view of compact prosecution, for the purpose of applying prior art, the arrowed bonds of the compound of Formula I are interpreted as having any type of special arrangement at these positions.
-The compounds of claims 6, 10, and 14 are prodrug compounds or salts of claim 1 and have the following structures:
PNG
media_image7.png
204
294
media_image7.png
Greyscale
,
PNG
media_image8.png
205
304
media_image8.png
Greyscale
, and
PNG
media_image9.png
203
303
media_image9.png
Greyscale
, respectively. However, the compound of claim 1 has the following structure:
PNG
media_image10.png
169
199
media_image10.png
Greyscale
. As such, it is not clear how the 8-membered, bridged nitrogen heteroring depicted in the compound of claim 1, is related as a prodrug to the compound of Formulas II or III or IV, since Formulas II-IV depict a spirocyclic piperidine attached to a hydantoin ring at the 8-membered, bridged nitrogen heteroring position of the compound of claim 1.
And further regarding Formulas III and IV, it is not clear how the fluorine substituted pyrrolizidine depicted in the compound of claim 1 is related as a prodrug to the compound of Formula III which depicts a fluroethylene group substituted at the fluorine position of the pyrrolizidine ring of claim 1, and it is not clear how the fluorine substituted pyrrolizidine depicted I the compound of claim 1 is related as a prodrug to the compound of Formula IV which depicts an ethylene group substituted at the fluorine position of the pyrrolizidine ring of claim.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
Claim Rejections - 35 USC § 112(a)-Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 18-20, and 35 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See MPEP 2163.
Independent claim 1 recites, “A prodrug of a compound of the following structure:
PNG
media_image11.png
169
199
media_image11.png
Greyscale
or pharmaceutically acceptable salt thereof.”
However, the specification only provides 4 sub-genuses of the prodrug of the compound of instant claim 1, wherein three of the sub-genuses do not share the same core structure with the compound of claim 1:
PNG
media_image12.png
208
225
media_image12.png
Greyscale
,
PNG
media_image13.png
204
294
media_image13.png
Greyscale
,
PNG
media_image14.png
205
304
media_image14.png
Greyscale
and
PNG
media_image15.png
203
303
media_image15.png
Greyscale
The specification exemplifies 80 compounds, wherein compounds 1-26 are those of Formula I, compounds 27-69 are those of Formula II, compounds 70-76 are those of Formula III, and compounds 77-80 are those of Formula IV. However, the specification only provides data on the stability of the compounds as prodrugs in Compounds 1-76 (Table 1, pgs. 182-138) , i.e., Formulas I-III and compounds 1-67 (Table 2, pgs. 185-186), i.e., Formulas I-II. Thus no data on compound IV is provided or any other prodrug outside the scope of compounds of Formulas I-III.
As seen in Tables 1 and 2, the t1/2(min) values range from 1 to >289 in compounds having the same core structure (compounds of Formulas I-III); compounds of the same core structure, have drastically different t1/2(min) values. Thus, it is not possible to determine a structure-function relationship amongst the prodrugs of the compounds of instant claim 1 or the prodrugs of Formulas I-IV that is critical to impart their usefulness as prodrugs of the compound of claim 1.
Bundgaard (Design of Programs, PTO-892) teaches that the necessary conversion or activation of prodrugs to the parent drug molecules in the body can take place by a variety of reactions (pg. 1). Several types of bio-reversible derivatives have been exploited for utilization in designing prodrugs (pg. 2).
Bundgaard teaches esters as prodrugs for compounds containing carboxyl and hydroxyl groups (pg. 3), teaches that sulphate esters of alcohols and phenols have long been considered as prodrug forms useful for obtaining injectable preparations (pg. 9), and that N-Mannich bases are useful prodrugs for NH-acidic compounds, such as amides, imides, carbamates, hydantoins and urea derivatives (pg. 10). Bundgaard further teaches n-hydroxymethyl derivatives, N-acyloxyalkyl derivatives, N-acyl derivatives, quaternary derivatives of tertiary amines, Schiff bases, enaminones, azo compounds, oxazolidines, 4-imidazolidinones, oximes, oxazolidines, thiazolidines, acetals, ketals, enol esters, barbituric acids, hydantoins, oxazolidinediones, lactones, derivatives of CH-acidic compounds, enzyme specified prodrugs of acyclovir, glycosidic prodrugs, and macromolecules such as proteins, nucleic acids, and antibodies, as prodrugs (pgs. 16, 21, 24, 36, 38, 39, 42, 43, 45, 47, 48, 51, 53, 55, 75-79).
Thus, the prior art teaches prodrugs as compounds containing chemical and biological groups ranging in structure and function from esters to macromolecules.
While [00056] of the specification defines prodrug as:
PNG
media_image16.png
337
633
media_image16.png
Greyscale
, this definition is not a limiting definition. [0056] generically defines prodrugs by what the do, but fails to define the instantly claimed prodrug as recited in claim 1.
As discussed in MPEP 2163II.A(3)(ii), the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A)above), reduction to drawing (see i)(B)above), or by disclosure of relevant identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. . .A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification only provides 4 possible generic compounds of “prodrug” wherein the disclosure, through preferred examples, teaches that prodrugs of a given compound can be compounds that do not even share the same core structures:
COMPOUND of CLAIM 1
PNG
media_image17.png
169
199
media_image17.png
Greyscale
DESCRIBED PRODRUGS OF THE COMPOUND
PNG
media_image18.png
208
225
media_image18.png
Greyscale
PNG
media_image19.png
204
294
media_image19.png
Greyscale
PNG
media_image20.png
205
304
media_image20.png
Greyscale
PNG
media_image21.png
210
309
media_image21.png
Greyscale
The species disclosed in the specification are very limited in scope when compared to the expansive scope of the “prodrug of a compound of
PNG
media_image22.png
169
199
media_image22.png
Greyscale
or a pharmaceutically acceptable salt thereof” recited in claim 1.
As a result, there is a vast scope in the claims that has no representation at all or homology to the disclosed species; the disclosure does not adequately reflect the structural diversity of the claimed genus of prodrug of
PNG
media_image22.png
169
199
media_image22.png
Greyscale
through the disclosure of sufficient species that are “representative of the full variety or scope of the genus.” In addition, there is no establishment of a reasonable structure-function correlation in the disclosure or the art.
Such a disclosure does not embrace widely variant species given the unpredictable nature of the art with respect to utility as evidenced by Tables 1 and 2 of the specification. Thus, a representative number of adequately described species were not disclosed for the genus such that one of skill in the art would reasonably conclude that the Applicant had possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 102
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 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.
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 1-3, 18-20 and 35 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2023/018812 to Yamano (effectively filed 08/10/2021, PTO-892).
Regarding claim 1, Yamano teaches the following prodrugs of the compound of instant claim 1.
PNG
media_image23.png
187
346
media_image23.png
Greyscale
(pg. 162, #15);
PNG
media_image24.png
481
344
media_image24.png
Greyscale
(pg. 173).
Regarding claims 1-3, Yamano teaches:
PNG
media_image25.png
139
171
media_image25.png
Greyscale
(pg. 177), which meets the limitations of instant Formula 1 when R1 is H and R2 is CH2-O-R3, wherein R3 is a C1 alkyl.
Regarding claim 18, Yamano teaches pharmaceutical compositions comprising its compounds in combination with a pharmaceutically acceptable excipient (pg. 326, claim 40).
Regarding claims 19-20 and 35, ‘Yamano teaches a method of treating cancer wherein one or more cells express KRAS G12D mutant protein, by administering an effective amount of its compounds to a subject (pgs. 327-329, claims 43-44, 48-55). Since Yamano teaches treating a cancer with KRAS G12D mutant protein, then the cancer has necessarily been determined to be associated with a wild type KRAS mutation.
Claim Rejections - 35 USC § 103
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 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.
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.
Claim 1-3, 5, 18-20 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2023/018812 to Yamano (effectively filed 08/10/2021, PTO-892).
Yamano is applied to claims 1-3, 18-20, and 35 as discussed above and incorporated herein.
Regarding claim 5, while Yamano teaches
PNG
media_image25.png
139
171
media_image25.png
Greyscale
, it differs from that of instant claim 5 in that it does not teach:
PNG
media_image26.png
462
231
media_image26.png
Greyscale
.
Yamano additionally teaches that its R6 position, the aryl substituent, can be substituted with a C1-4 alkoxy (pgs. 278-279, claim 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the chain length of the alkyl group in the alkoxy group of
PNG
media_image27.png
139
171
media_image27.png
Greyscale
of Yamano, to arrive at
PNG
media_image28.png
462
231
media_image28.png
Greyscale
. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success because:
-Yamano teaches that the length of its alkyl groups in its alkoxy groups can be modified in length from C1 to C4, and
-Compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.), MPEP 2144.09.
As such, an ordinary skilled artisan would have been motivated to make such a modification to predictably arrive at a structurally and functionally similar compound.
Free of the Prior Art
Claims 4 and 6-17 are free of the prior art.
The closest prior art is WO 2023/018812 to Yamano, whose teachings are detailed above.
Yamano additionally teaches compounds such as:
PNG
media_image29.png
135
152
media_image29.png
Greyscale
.
However, Yamano does not teach a compound of instant Formula I wherein R1 is H and R2 is selected from the groups recited in instant claim 4, and Yamano does not teach compounds of instant Formulas II-IV, wherein the piperidine is spirocyclicly bound to a hydantoin ring.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LAUREN WELLS/Primary Examiner, Art Unit 1622
Prosecution Insights