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 amendment filed February 18, 2026, is acknowledged and has been entered. Claims 1-4, 30-34 and 39-40 have been amended.
Claims 1-4 and 25-40 are pending in the application and under examination.
Applicant has elected compounds of Formula (I) which have substituents as follows:
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Grounds of Objection and Rejection Withdrawn
Unless specifically reiterated below, Applicant's amendment and/or arguments have obviated or rendered moot the grounds of objection and rejection set forth in the previous Office action.
Claim Rejections Maintained
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-4 and 25-40 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The teachings of the specification and the claimed invention:
As amended, the nature and scope of the claimed invention at issue is a genus of methods comprising:
administering to a patient, an anti-tumor composition including; an effective amount of a small molecule integrin agonist in an integrin agonist carrier, and a therapeutically effective amount of effector cells, wherein the effector cells comprise tumor infiltrating lymphocytes (TIL); T-cell clones reactive to one or plurality of tumor antigens; T-cells genetically engineered with tumor specific-T-cell receptors or chimeric antigen receptors; and natural killer cells reactive to a specific or plurality of tumor antigens in an aqueous cell carrier medium wherein the small molecule integrin agonist stabilizes the integrins including α4β1, α4β7, α5β1, αLβ2, αVβ3, or combinations thereof in their high affinity state and
increases interactions between the effector cells and ligand expressing cells including one or more
ligands for the integrins resulting in improved effector cell infiltration into solid tumor stroma and
enhanced anti solid tumor effector cell activity of the effector cells, and wherein the one or more ligands comprise VCAM-1, fibronectin, MadCAM-1, ICAM-1, ICAM-2, vitronectin, or any combination thereof.
(see claims 1 and 31).
Claims 29 and 39 recite that the composition includes a of a genus of a small molecule integrin agonist comprising a compound of the general Formula (I) R1- M1 -N(R2)-M2 - M3 - M4 - M5 - M6 – R3 :
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as drawn to the elected species and claims 30 and 40 recite lists of small molecules for use in the claimed methods.
The instant specification discloses in the examples starting at page 53 that compound (methyl(6S, 1 OS)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate), is a small molecule that acts as a VLA-4 activator. The instant specification has not disclosed that the genus of small molecule integrin agonists/activators as claimed stabilize integrins including α4β1, α4β7, α5β1, αLβ2, αVβ3, or combinations thereof in their high affinity state resulting in improved effector cell infiltration into solid tumor stroma and enhanced anti solid tumor activity of the effector cells, or that the other small molecules of claims 30 and 40 stabilize integrins including α4β1, α4β7, α5β1, αLβ2, αVβ3, or combinations thereof in their high affinity state resulting in improved effector cell infiltration into solid tumor stroma and enhanced anti solid tumor activity of the effector cells. Notably, the claims recite administering an effective amount small molecule integrin agonists/activators for enhanced anti-solid tumor effector cell activity, but the specification does not test any small molecule integrin agonists/activators for enhanced anti-solid tumor effector cell activity.
State of the Art
With respect to the claimed genus of small molecule integrin agonists/activators, it is noted that the genus of activators is widely diverse and one could not immediately envision, recognize or predict the structure of small molecule integrin agonists/activators which would have anti-tumor activity, from those that would not. For example, Dzobo, Kevin (OMICS, 25(7):417-430, 2021, of record) teach integrins play a role in promotion of cell adhesion and invasion and drug resistance such that integrin antagonists are under clinical trials to treat cancer. Dzobo also points out that anti-integrin therapy relies heavily on doses or concentration because these determine whether the drugs act as antagonists or agonists (see abstract).
Furthermore, Biediger et al (WO 2012/068251 A2, IDS) disclose an integrin agonist (3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4, 7, 10-trioxa-2-azadodecan-12-yl bis(2-thienylmethyl)carbamate which is a species of compound encompasses by Applicant’s species election as set forth by Applicant on page 28 of their response filed March 20, 2023. This compound also has the name (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(bis(thiophen-2-ylmethyl)carbamate) and has the following structure:
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as a small molecule integrin agonist that can be administered along with effector cells to patients that would appear to have the claimed function based its activity in Biediger et al.
Accordingly, small molecule integrin agonists are widely diverse and one of skill in the art would not be able to recognize which small molecule integrin agonists encompassed by the claims would stabilize integrins including α4β1, α4β7, α5β1, αLβ2, αVβ3, or combinations thereof in their high affinity state resulting in improved effector cell infiltration into solid tumor stroma and enhanced anti solid tumor activity of the effector cells.
Claim Analysis
The nature and scope of the claimed invention is set forth above.
First there are claims drawn to small molecule integrin agonists of any structure, while the other claims require the “agonists” to have structures of Formula (I), it is apparent the claims encompass structurally diverse “compounds” that must also stabilize integrins including α4β1, α4β7, α5β1, αLβ2, αVβ3, or combinations thereof in their high affinity state resulting in improved effector cell infiltration into solid tumor stroma and enhanced anti solid tumor activity of the effector cells. Then claims 30 and 40 recite small molecules where that are clearly defined by their independent structure, but the specification does not identify the particular structure shared by the claimed compounds which result in stabilizing integrins including α4β1, α4β7, α5β1, αLβ2, αVβ3, or combinations thereof in their high affinity state resulting in improved effector cell infiltration into solid tumor stroma and enhanced anti solid tumor activity of the effector cells to provide evidence that each compound is an integrin agonist.
Notably, one of skill in the art would not consider the disclosure of compound (methyl(6S, 1 OS)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate) as a small molecule that acts as a VLA-4 activator as representative of the claims because these genera includes members which do not share the same structural or functional attributes. Accordingly, one of skill in the art would reasonable conclude that applicant was not in possession of the claimed “agonists” that have the recited function. In this case, the specification theorizes at page 55 that (methyl(6S, 10S)-10- (1,3-benzodioxol-5-yl)-6-butyl -3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9- triazadodecan-12-oate) may be particular preferred stabilizer of effector cell and endothelial interactions for solid tumors where such adhesion pathways are down regulated and that the potency and efficacy of ACT using effector T-cells could be improved by pre-treating the cells with compounds such as AEC 1(methyl(6S, 1OS)-10-(1,3-benzodioxol-5-yl)-6- butyl -3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan- 12-oate) that improve tumor endothelial cell adhesion and transmigration which could facilitate the infusion of fewer effector cells without comprising anti-tumor activity. However, this theory does not point to the particular structure that is required to be a VLA-4 activator and that specification does not contain evidence that the genus of claimed compounds would be expected to have anti-tumor activity in vivo by themselves as the anti-tumor activity is not tested.
To further explain why the claims which recite structurally and functionally diverse small molecule “agonists” and activators” with anti-tumor activity are not adequately described, it is noted that it is well-established in the art that there is a high degree of unpredictability in modeling and predicting agents which will bind to any particular protein. For example, according to Tame (J. Comput. Aided Mol. Des. 1999 Mar; 13 (2): 99-108, IDS), computational approaches to design or select drug reagents which bind protein targets are hindered by the complexity of the physical chemistry that underlies weak, non-covalent interactions between protein targets (e.g., a cell surface receptor) and small molecule ligands (e.g., peptides); see entire document (e.g., the abstract). In addition, Dixon (Proteins. 1997; Suppl 1: 198-204, IDS) points out that the evaluation (scoring) of potential solutions is still an area that needs improvement, especially when predicting protein-protein interaction because of limitations associated with reproducing the geometry of the complex; see entire document (e.g., the abstract). While there are many additional reasons that predictions based upon the results of such modeling approaches are inaccurate, it is noted that Lensink et al. (Proteins. 2007; 69: 704-718, IDS) reviewed the performance accuracy of various different methods for predicting protein-protein interaction, reporting that significant numbers of "incorrect" determinations were made in blind analyses (i.e., without knowledge of the “correct” answer); see entire document (e.g., page 706, Table I). Lensink et al. concludes accordingly that their results "do not reveal a striking breakthrough in docking performance" in the past several years, despite some encouraging progress (page 717, column 1); and given such predictive inaccuracies, Lensink et al. adds that “current scoring methods are probably not sensitive enough” (abstract).
As such, while the specification describes compound (methyl(6S, 1 OS)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-l-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7,9-triazadodecan-12-oate), as a small molecule that acts as a VLA-4 activator, and the prior art discloses (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(bis(thiophen-2-ylmethyl)carbamate) as another integrin agonist that would appear to function similarly in the claimed methods, such constructs are not representative of the respective genera, as a whole, since there is no disclosure of a correlation between any one particularly identifying (i.e., substantial) structural feature, which is shared by these species and other members of their respective genera, and any one functional feature also shared by at least most of the other members of their respective genera.
Consequently, the skilled artisan could not immediately envision, recognize or distinguish at least most of the members of the genera of “integrin agonists” that have the recited function to which the claims are directed; and therefore, the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
Starting at page 30 the response, Applicant has traversed the rejection.
Applicant’s arguments and the declaration have been carefully considered but are not found persuasive for the following reasons:
In the response, Applicant argues that “Subsequent to the Biediger filing date, the inventors also tested many of the Formula (I) integrin agonists for LFA-1, which were found to have similar LFA-1 EC50 values to methyl(6S, 10S)-10-(1,3-benzodioxol-5-yl)-6-butyl-3,8-dioxo-I-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7.,9- triazadodecan-12-oate and (3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10-trioxa-2-azadodecan-12-yl bis(2-thienylmethyl)carbamate or ethane-1,2-diylbis(oxy)bis(ethane-2,1-diyl)bis(bis(thiophen-2- yl methyl)carbamate.
As the Biediger integrin agonists, the integrin agonists of Formula(I) of this application, were known compounds to have similar activities for enhancing integrin expressing cells interactions with cells expressing the integrin ligands, Applicant is relying on the disclosure of Biediger for the proposition that the integrin agonists of Formula (I) are effective in enhancing integrin expressing cells interactions with cells expressing the integrin ligands. Additionally, the Biediger published application was incorporated by reference in the present application.”
In response, this argument is not found persuasive because the claims are drawn to methods of treatment that results in enhanced anti solid tumor effector cell activity using a structurally diverse genus of small molecule integrin agonists and the response to the rejection does not articulate how the compounds of Biediger and the compounds of the instant application are representative of the claimed genus of other structurally unrelated small molecule compounds. Here since structurally unrelated compounds are included in the claimed genus but the specification does not include disclosure of other structurally unrelated small molecule compounds with enhanced anti solid tumor effector cell activity, it is maintained that the disclosed species of the specification and Biediger are not representative of the claimed genus. Notably, claims 1 and 31 do not require “the integrin agonists of Formula (I)” as set forth in Applicant’s argument such that the disclosed compounds would not be considered representative. Then with respect to all the claims, because the claims recite administering an effective amount of small molecule integrin agonists/activators for enhanced anti-solid tumor effector cell activity, but the specification does not test any small molecule integrin agonists/activators for enhanced anti-solid tumor effector cell activity, the disclosed compounds would not be considered representative of each and every compound encompassed by the claims as having the function of enhanced anti-solid tumor effector cell activity.
Therefore, after careful and complete consideration of Applicant’s response and the record as a whole, for these reasons and the reasons of record as explained in the preceding Office action, this rejection is maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner can normally be reached on Monday through Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
March 12, 2026