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 the Claims
Claims 1-2, 5-6, 9-10, 13-15, 17-19, 21, 26-31 are currently pending in the Application with claims 2, 14, 15, 17-19, 21, 31 currently withdrawn. Therefore claims 1, 5-6, 9-10, 13, 26-30 are examined on the merits below.
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 (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.
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.
Claim(s) 1,5, 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Baeuerle et al (WO2017156178), cited in IDS 07-01-2025 foreign reference #10. The disclosure of Baeuerle discloses “inducible binding proteins and methods of use” as a single molecule which are conditionally activated polypeptide constructs as exemplarily illustrated in the reference claim figure 3 below (title, abstract, figure 3).
PNG
media_image1.png
612
959
media_image1.png
Greyscale
As in figure 3 for example the agent of Baeuerle is initially formed as a single polypeptide chain. Anticipating claim 1 (i)(a) the agent comprises a “first targeting moiety” which binds a tumor antigen expressed by a cancer as “anti-EGFR G8 sdAb” which is an antibody or antigen binding fragment thereof. Reading from N terminal (“N”) to C terminal (“C”) in figure 3 and comparable to claim 1(ii) and 1(iii) and 1(iv) the single molecule “comprises” an anti-CD3 scFv as a first T cell engaging domain (VH) and an inert binding partner (VLi). Regarding claim 1(v) the disclosure of Baeuerle comprises a protease cleavage site for enterokinase protease (“EK cleavable linkers”) between the “activatable” anti-CD3 scFv VH domain and the inert VL domain (masking moiety). Enterokinase is characterized by Baeuerle as protease which may be expressed by a variety of tumor or cancer cells as a type of diseased cells and tissues (00256-00257, table 1) . Similarly regarding the second targeting moiety (instant claim 1(vi) through 1(vii)) which is capable of targeting the cancer, the agent of figure 3 of Baeuerle additionally comprises a second targeting moiety as “D12 sdAb” which targets the cancer, and a ½ component CD3 binding VL which is “masked” by and inert VH (VHi). Thus the disclosure of Baeuerle “comprises” as a single molecule in figure 3 prior to enzymatic cleavage an agent species which is fully encompassed by the instant claim 1 (anticipates).
Regarding the instant claim 5 as indicated in figure 3 of Baeuerle a linker attaches the first and second inert binding partners in this specific embodiment of the disclosure.
Regarding the instant claim 13 the “targeting moieties” of the disclosure of Baeuerle are all considered antibody or antigen binding fragment thereof as scFv molecules or single domain antibody.
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.
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(s) 6, 9, 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle.
Regarding the instant claims 6, 9 the disclosure of Baeuerle (figure 3) does not describe that “the linker” comprise a ½ life extending “moiety” or that the moiety comprises all or part of an immunoglobulin constant (Fc) domain. However the disclosure of Baeuerle is comprehensive and does recognize the utility of providing for ½ life extending moiety on single molecule constructions/variations of the targeting agents disclosed. Baeuerle describes that in-vivo half-life extension domains are preferably positioned to allow for removal of the domain once they have been delivered to the appropriate site (tumor) through linkage to the remainder of the molecule (initial fusion protein construct) through one or more cleavable linkers (0009)(00151)(00227). Furthermore the disclosure of Baeuerle describes specifically that half-life extension domain may comprise an Fc domain (00216). It would therefore be obvious to provide an agent which further comprises an Fc domain as a half-life extension domain which “optionally” may be linked to other components of the agent in such a fashion so that the domain is cleaved and separated from the active agent(s) once it is delivered to a location such as a tumor microenvironment. As explained by Baeuerle one would do so for the purposes of allowing for increased therapeutic half-life in-vivo in blood while at the same time providing facilitated concentration and activation of the original inactive agent within specific target sites in the organism such as a tumor site.
In the new instant claim 26 Applicant adds a partial order-structure to the instant claim 1. Regarding the claim 1, 26 the disclosure of Baeuerle provides a variety of permutations of the molecule which are provided in the figures 3, 53 as “prodents”. At least 46 different exemplary variations of the prodent molecules are provided (figures 53-55). Baeuerle further provides exemplary fusion protein construct schematic as provided in (00228-00229). The disclosure of Baeuerle describes a particular prodrug composition in (00230-00232) which comprises first and second polypeptide regions which satisfy the limitations of the instant claim 26. See also embodiment “c” of paragraph 00228 among others. In as much as the citation indicates that the composition is comprised of two polypeptide chains, the disclosure of Baeuerle is clear that the composition of the invention may preferably be initially comprised in a single polypeptide chain as in figure 3, 53 or as separate preactivated peptide chains depending on the desired outcome. It would be obvious therefore to provide the indicated partially described structure of claim 26 as a composition in a single polypeptide chain as a composition which is previously disclosed and presented as useful by the disclosure of Baeuerle.
The instant claim 27 further describes that “the linker” may actually comprise also a half-life extending moiety. As indicated for the instant claim 1 the disclosure of Baeuerle provides that half-life extending moiety may be utilized in composition of the disclosed molecules. As exemplified in figure 3,53 and (00228) the disclosure of Baeuerle provides half-life extension domain located at a variety of points within single molecule of the invention. It would be obvious to provide such domain as part of the instant claim 1-26-27 for the purposes as explained above of providing enhanced in-vivo circulating half-life of the inactive molecule while allowing for simultaneous removal of the “linker-half-life extending moiety” through localized proteolytic cleavage and conditional release/activation at the site of a tumor for example.
The instant claim 28 describes a fusion protein which in addition to the components of the claim 26 also comprises at N terminal location of the 1st and 2nd halves of the fusion protein the first and second halves of an Fc domain. As described above the disclosure of Baeuerle describes that Fc domain may be utilized as half-life extending domains (0216). Additionally Baeuerle provides a variety of constructs that are contemplated as described in figure 53. Of particular relevance to the instantly claimed molecule of claim 28, Baeuerle provides the figure 53E (below) in N-C orientation that comprises the elements of the instant claim 28, in particular order as claimed with “HED” representing half-life extension domain (0229, 0136).
PNG
media_image2.png
104
1050
media_image2.png
Greyscale
Therefore the disclosure of Baeuerle indicates the generic structure instantly claimed as in figure 53E including N-terminal half-life extension domains of 1st and 2nd regions of a fusion protein. Baeuerle additionally indicates that Fc regions of immunoglobulin may be utilized as half-life extending domains (00216). It would be obvious to provide the instantly claimed structure including the Fc domain halves as half-life extending domains for the purposes of providing a molecule with improved pharmacokinetic properties in-vivo, and improved concentration/delivery of the active molecule at the site of a tumor for example.
Instant claim 29 describes that the Fc half-life extending domain comprises the sequence of a human immunoglobulin. The disclosure of Baeuerle provides that preferably antibody of the invention are humanized and that such antibody would optimally comprise at least a portion of an immunoglobulin constant region, typically that of a human immunoglobulin (0170-0172). It would thereby be obvious to utilize a human Fc region as a half-life extending domain for the purposes of providing a molecule which would provide functional FcRn binding in-vivo in humans, thus providing extended in-vivo half-life of the molecule.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle as applied to claim 1 above, and further in view of Wang et al (Protein Cell 2018, 9(1):63–73).
The disclosure of Baeuerle is indicated above. Baeuerle does not describe particular mutations to an Immunoglobulin Fc region such as in claim 10, (i) or (ii). The further disclosure of Wang describes a number of modifications to antibody Fc regions that have been described over the years that result in a variety of desirable enhancements to Fc characteristics depending on the particular need of an inventor (table 1). Among the modifications presented are changes which increase the ½ life of an Fc molecule that comprises them including a residue 252, 254, 256 mutation from wild type to “YTE” respectively. It would be obvious to utilize the mutations of Wang in Fc fragments of Baeuerle for the purposes of increasing FcRn binding of the circulating therapeutic molecule thereby facilitating a beneficial longer in-vivo half-life of the molecule compared to molecules comprising the wildtype Fc molecule.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle as applied to claim 29 above, and further in view of Wang et al (Protein Cell 2018, 9(1):63–73). The disclosure of Baeuerle is indicated above. Baeuerle does not describe particular mutations to an Immunoglobulin Fc region such as in claim 30. The further disclosure of Wang describes a number of modifications to antibody Fc regions that have been described over the years that result in a variety of desirable enhancements to Fc characteristics depending on the particular need of an inventor (table 1). Among the modifications presented are changes which increase the ½ life of an Fc molecule that comprises them including a residue 252, 254, 256 mutation from wild type to “YTE” respectively. It would be obvious to utilize the mutations of Wang in Fc fragments of Baeuerle for the purposes of increasing FcRn binding of the circulating therapeutic molecule thereby facilitating a beneficial longer in-vivo half-life of the molecule compared to molecules comprising the wildtype Fc molecule.
Response to Arguments- Claim Rejections – 35 USC § 103
In response to Applicant’s arguments and amendments to the instant claims which describe that the agent of interest is comprised as a single molecule the previously applied rejection is withdrawn. Additional rejections over the disclosure of Baeuerle are provided.
Response to Arguments- Claim Rejections – 35 USC § 112
In response to applicant’s amendment to the instant claim 1 the previously applied rejection under 35 USC § 112a-written description is withdrawn.
Conclusion
Summary: No claims are allowed.
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 07-01-2025 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN HARTNETT whose telephone number is (571)272-3077. The examiner can normally be reached Monday-Friday 8:00 AM - 5:00 PM EST.
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, Daniel E Kolker can be reached at 571-272-3181. 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.
/BRIAN HARTNETT/Examiner, Art Unit 1644
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671
Prosecution Insights