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
Status of the Claims
1. Claims 1-28 are the original claims filed 4/14/2021. In the Preliminary Amendment of 8/10/2021, Claims 1-28 are canceled and new Claims 29-67 are added. In the Response of 12/13/2023, Claims 29-67 are canceled and new Claims 68-83 are added. In the Response of 7/12/2024, Claims 68 and 77 are amended and Claim 78 is canceled. In the Response of 3/6/2025, no claims are amended, canceled or added.
Claims 68-77 and 79-83 are all the claims.
Priority
2. USAN 17/230,240, filed 04/14/2021, and having 1 RCE-type filing herein is a Divisional of 14/340,872, filed 07/25/2014, now U.S. Patent # 11161906 and having 4 RCE-type filings therein, and 14/340,872 Claims Priority from Provisional Application 61/858,402, filed 07/25/2013.
Information Disclosure Statement
3. As of 4/22/2025, a total of six (6) IDS are filed for this application: 4/14/2021; 1/6/2023; 6/6/2032; 12/6/2023; 12/21/2023; and 11/13/2024. The corresponding initialed and dated 1449 form is considered of record.
Rejections Maintained
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.
Written Description
4. The rejection of Claims 68-77 and 79-83 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 is maintained.
The attorney comments and the affidavit statements are a re-iteration of the other and add no further information than what is taught in the specification for the literal elements comprising the literal probody structures shown in the reproduced figure of the body of the response and the affidavit.
Response to Arguments
The multispecific activatable antibody of the claimed invention, having acquired the art-recognized meaning as a “prodrug” platform, is under clinical trial testing for the corresponding species SUCH AS CX-072 (anti-PD-L1), CX-2029 (anti-CD71), and CX-2009 (anti-CD 166). These and other studies of prodrug platforms have revealed the unpredictability of the structure with the alleged function.
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability” (citing In re Marzocchi, 439 F.2d 220, 223-24, 169 USPQ 367, 369-70 (CCPA 1971)).
“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
The POSA recognizes that probody technology faces challenges related to the control and reliability of drug release in the tumor microenvironment, potential on-target toxicity, and the potential for drug effect loss due to strong shielding and binding.
Autio et al (Clin Cancer Res (2020) 26 (5): 984–989) does not overstate the applicability of the prodrug platform against any antigen using an CM/MM pair within a general meaning of the multispecific activatable antibody. Autio specifically defines the prodrug CX-072 having the structure of “three modular components—an active anticancer monoclonal IgG antibody or fragment of a variable region, a masking peptide linked to the N-terminus of the light chain, and a protease-cleavable substrate linker peptide— produced as a single protein using recombinant antibody production methodology (Fig. 1; refs. 31, 32).”
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Absent a showing to the contrary, none of the protypes in development by CytomX deviate from the structure depicted in the figure.
Autio teaches that prodrug therapy shows promise for only those protypes tested within the construct of figure 1 for a narrow number of species: “Probody therapeutics are a new approach to overcome the AE challenges of immunotherapy because their activation is designed to be restricted to the TME. Therefore, systemic toxicity should be limited, risk-benefit improved, and more potent combination therapies may be exploited.” The POSA could reasonably conclude based on Autio, that the possession of the myriad species of component elements for the probody of the invention as alleged by Applicants in their response and the affidavit, is merely a wish to have.
See MPEP 2163 (II)(3)(a):
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
MPEP 2163 (II)(3)(a)(i):
Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing “a result that one might achieve if one made that invention”); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does “little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate”).
www.bocsci.com/blog/probody-antibody-prodrug-technology teaches the difficulties of the current probody technology are as follows. First, the release of the drug in the tumor microenvironment is uncontrollable; second, pro-ADC cannot perfectly solve the on-target toxicity. Its shielding and binding ability is too strong, and the drug effect will be lost. It can only be done appropriately attenuate. Therefore, the dilemma of Probody technology is that as soon as it is effective, there will be toxicity. There are two kinds of toxicity, one is on target toxicity, and the other is payload toxicity. From this point of view, the current Probody technology is difficult to make a big difference in curative effect, and further research by scientific researchers is needed.
Boustany et al (Cancer Res 2022 Nov 15;82(22):4288-4298) mentions caveats of the prodrug therapy as whole:
“Notably, Probody therapeutics are not inert molecules as the interaction between the mask and antibody is dynamic and the mask has both bound and unbound states. Therefore, at high concentrations of intact Probody therapeutic, some target binding and functional activity is expected.”
“Notably, many patient tumors exhibit immunosuppressive tumor microenvironments with poor T-cell infiltration (33, 34), which are expected to hinder activity of this modality. To increase the potential for clinical benefit, indications with high EGFR expression and inflamed tumor microenvironments such as non–small cell lung cancer could be selected.” Here Boustany specifically teaches away from Applicants allegations for the universality of the prodrug construct using any antibody-based antigen-binding aspect to target any antigen.
“Evaluation of safety in mouse models would be a valuable approach to define the efficacy and/or safety balance of Probody TCBs; however, this requires mouse models in which both the target and CD3 are humanized because of the lack of rodent cross reactivity of CI107.”
The POSA would readily recognize that the breadth and scope of Applicants allegations measured against what Applicants have shown to work for the probody construct and in further view of what the field of art recognizes as the caveats to the technology, do not qualify as meeting the structure/function correlation under the written description guidelines. The rejection is maintained.
Conclusion
5. No claims are allowed.
6. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643