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 .
Applicant filed a response to the Non-Final Action of 4/27/2023 on 10/26/2023.
Status of the Claims
Claims 1-74 are canceled. Claims 75-87, 92 are amended. Claims 94-97 are new. Claims 75-97 are under consideration.
Withdrawn Objections/Rejections
Objection to Drawings
Applicant filed amendments to the Drawings and updated the Specification. The objection is withdrawn.
Objection to Claims
Applicant amended the claims to address the objections. The objection to the claims is withdrawn.
112(b)
Applicant amended the claims to address the rejections. The rejections are withdrawn.
112a, Written Description
The rejection of 4/27/2023 has been withdrawn and a new rejection has been written.
112a, Scope of Enablement
The claims were rejected under scope of enablement as there was enablement for SEQ ID NOs: 195, 198, 199 or variants of SEQ ID NOs: 198 and 199 that comprise one or two amino acid substitutions. The rejection of these claims has been withdrawn.
New/Maintained Rejections
Claim Rejections - 35 USC § 112
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 75-93 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.
Regarding claim 75, the claim is drawn to separation moieties of SEQ ID NOs: 195-198, 200 and functional variants of SEQ ID NOs: 195-198, 200, wherein the functional variants comprise 1-3 amino acid substitutions. The specification and the art do not provide written description support for the breadth of the mutations encompassed by the claims.
At the time the invention was made, Song et al., 2019, iProt-Sub: a comprehensive package for accurately mapping and predicting protease-specific substrates and cleavage sites, Briefings in Bioinformatics, 20: 638–658, teach that knowledge of the mechanisms that regulate and control the proteolytic processing of proteases remains limited. The precise understanding of the biological function of a protease requires the identification of the complete repertoire of its natural substrates and corresponding substrate cleavage sites. The specificity of proteases can vary significantly, depending on the protease and the active sites, with the cleavage site selectivity ranging from references for limited and specific amino acids at specific positions, to more general preferences with little discrimination. There are current experimental methods for proteolytic cleavage and quantitation methods for proteolysis to better understand the dynamics and extent of proteolytic events such as the TAILS method. Despite the advances of these experimental methods, they are labor intensive, expensive, and time-consuming and are often limited to the investigation of one protease each time (Song et al, page 639, 1st col, 2nd parag.).
Parag. 0017 of the specification teaches that sequences were selected from a diverse peptide library as substates for proteases with mass spectrometric detection of protease cleaved products to identify preferred sequence motifs for each candidate protease. Thus, similar to what Song et al. teach, the specification teaches that one obtains peptides cleaved by proteases by screening. The screen identified SEQ ID NOs: 195-198, 200 and a number of mutants of SEQ ID NO: 195 and 197.
Regarding claims 95-97, SEQ ID NOs: 195-198, 200 have written description support as the specification correlates the structures to the digest sites: SEQ ID NO: 195 (MMP15), SEQ ID NO: 196 (MMP2/9), SEQ ID NO: 197 (CTSL1), SEQ ID NO: 198 (CTSL1), SEQ ID NO: 200: (ADAM17).
Sequences that were identified to be mutations of SEQ ID NOs: 195, 198, 200 and still be digestible by MMP15 (SEQ ID NO: 195), CTSL1 (SEQ ID NO: 198), ADAM17 (SEQ ID NO: 200) were provided in the specification.
MMP15:
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524
986
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In the case of digest sites for MMP15, relative to SEQ ID NO: 195, there is WD support for
one amino acid substitution:
GPAGL#AQ
two amino acid substitutions:
GP#GLKAQ
GPANLVAQ
GPANLRAQ
GPAGLRGA
GPAGLKGA
GPLGL#AQ
GPLGLYGA
three amino acid substitutions:
#PLGLKAQ
GPLGLK#Q
GPLGLKA#
(where underlining indicates an amino acid different from SEQ ID NO: 195 and # is any amino acid).
CTSL1:
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500
1242
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In the case of digest sites for CTSL1, relative to SEQ ID NO: 198, there is WD support for
one amino acid substitution:
ALFKSS#P
two amino acid substitutions:
#LFKSSPP
A#FKSSPP
AL#KSSPP
ALF#SSPP
ALFK#SPP
ALFKS#PP
ALFKSSP#
three amino acid substitutions:
none
(where underlining indicates an amino acid different from SEQ ID NO: 198 and # is any amino acid).
Written description support for 2 mutations in ADAM17 digest site (SEQ ID NO: 200) is limited to SEQ ID NO: 201.
ADAM17:
SEQ ID NO: 200 LAQRLRSS
201 LAQKLKSS (also target of ADAM10, identified in WO2003106381, see art rejection, below)
Claims 84-86 are drawn to protease sites that have greater catalytic efficiency, greater specificity, or reduced catalytic efficiency. In looking at the sequences above that were identified as digestion sites, neither the specification nor the art provides guidance as to which (if any) of the sequences identified by applicant have greater catalytic efficiency, greater specificity, or reduced catalytic efficiency. Further, given that the art teaches that one cannot predict sequences that are targets for proteases, the converse is true that one cannot predict the sequences that are identified as protease targets also have additional functional features such as greater catalytic efficiency.
Thus, the state of the art and the specification with regard to predictably correlating protease digestion sites that comprise amino acid residues different from the original sequence and function (i.e. a protease target site) was not known. Rather, the art and the specification teach that the way to obtain sequences that function like the original and comprise different amino acids is to perform an iterative process of making the peptides, carrying out the assay, and identifying candidates that are positive for a characteristic screened in the assay. Carrying out a screening method to identify products that have the required characteristics recited in the claim does not address written description. Rather, possession (either structure, or a reliable way of creating structure) must be shown at the time of filing, see MPEP2163.
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.
Claims 75-78, 82-87, 91, 92 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 11406710 (May et al.).
May et al. teach that novel constructs that are selectively activated in the presence of tumor proteases (May et al., col. 1, 3rd parag. under Background of the Invention). May et al., Figure 1, teach a linear construct that comprises an anti-tumor target antigen (anti-TTA) antibody, a linker, an anti-CD3 VH domain, a cleavable 8mer linker, an anti-CD3 VL domain, a linker, an anti-TTA, a cleavable linker, a CD3 VL pseudodomain, a cleavable 8mer linker, an anti-CD3 VH pseudodomain, a linker, and human serum albumin (HSA). The pseudo variable domains comprise CDRs that do not form functional anti-CD3 antibodies. The linear construct folds into a constrained formation where the 8mer linker is too short to allow the functional anti-CD3 heavy and light variable domains to interact with each other. The pseudo heavy anti-CD3 variable domain interacts with the functional light anti-CD3 variable domain and the pseudo light anti-CD3 variable domain interacts with the functional heavy anti-CD3 variable domain. Interaction of the variable domains with a corresponding pseudo variable domain results in non-functional anti-CD3 antibody. The constrained format prevents off-target toxicities (May et al., col. 11, starting at line 60). Protease digestion allows release of the therapeutic construct, an anti-CD3 fused to 2 anti-TAAs.
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212
790
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Regarding claim 77, wherein the polypeptide comprises 2 or more separation moieties, May et al. teach three cleavable linkers in their construct, Figure 1. One is located between CD3VH and CD3VL, the second is between alpha-TTA and CD3VLpseudo, and the third is between CD3VLpseudo and CD3HVpseudo.
Regarding claim 83, the half-life extension domain, May et al. teach human serum albumin (Figure 1, legend).
Regarding claims 75, 84-86, wherein the separation moiety is cleaved with either greater catalytic efficiency, or reduced catalytic efficiency, May et al. teach in Figure 5F, the MMP2/9 cleavable linker, SEQ ID NO: 75 and also, high and low efficiency MMP9 variants, May et al.’s SEQ ID NO:s 90 (GPAGMHGL) and 91 (GPAGMEGL). It is noted that May SEQ ID NOs: 90 and 91 address the limitation of one amino acid is substituted, in claim 75.
It would have been obvious for an artisan before the effective filing date to use the MMP9 cleavable linker in their construct shown in Figure 1. One would have done so because May et al. teach that the MMP9 cleavable linker is one of a number of linkers that can be used to digest their construct at the site of cancer.
Claims 75, 76, 80-82, 87, 89-92 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 10822419 (Wang et al.) in view of US Patent 11406710 (May et al.).
Wang et al. teach an activatable mCAR that is inactive when masked and active when unmasked (Wang et al., col. 1 under Field of Invention). Wang et al. teach that CAR T cells have the potential to generate very high levels of anti-tumor activity, but they also may display off-target cell killing (Wang et al., col. 2, lines 17-27). Wang et al. teach in Figure 1A, that in an environment with no cancer, the mask covers the antibody. In the tumor microenvironment, in the presence of proteases, the masking peptide is cleaved and the previously blocked antigen-binding site of the single chain variable fragment (scFv) is exposed. Wang et al. teach a number of cleavable linkers recognizable by proteases are known (Wang et al. col. 13, lines 19-41).
While Wang et al. teach a cleavable linker, they do not specifically teach SEQ ID NO: 196.
May et al. teach SEQ ID NO: 75, which is the same as instant case’s SEQ ID NO: 196. These cleavable linkers are digestible by enzymes found at a tumor site (May et al., abstract).
One would have used May et al.’s SEQ ID NO: 75 as Wang et al.’s cleavable linker. One would have done so because May et al. tech that SEQ ID NO: 75 functions as a cleavable linker for MMP9, a protease found at the site of tumors.
Claims 75, 76, 79, 87, 88, 92 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 8734774 (Frelinger et al.), in view of Ozden et al., 2013, Expression of MMP-1, MMP-9, and TIMP-2 in prostate carcinoma and their influence on prognosis and survival. J. Cancer Res. Clin. Oncol., 139: 1373-1382, and US Patent 11406710 (May et al.).
Frelinger et al. teach chimeric fusion peptides that could be cleaved by a tumor cell expressed protease, based on steric hindrance. The strategy used two biologically active molecules, cytokine IL-2 and the Macrophage inflammatory protein 1 alpha (Mip1alpha) separated by a very short peptide sequence recognized by the prostate specific proteinase, PSA (Frelinger et al, Example 1 and Figure 1).
While Frelinger et al. teach the use of PSA proteinase site that was used to connect IL-2 and Mip1alpha, they do not teach an MMP-9 cleavage site.
Ozden et al. teach that MMP-9 is expressed in prostate carcinoma (Ozden et al., Title).
May et al. teach SEQ ID NO: 75, which is the same as instant case’s SEQ ID NO: 196. These cleavable linkers are digestible by enzymes found at a tumor site (May et al., abstract).
It would have been obvious for an artisan before the effective filing date to substitute Frelinger et al.’s PSA proteinase site with an MMP9 proteinase site. One would have done so because MMP9 is also expressed in prostate cancer and can be used to cleave Frelinger et al.’s construct. There would have been reasonable expectation of success as the PSA proteinse site is functionally equivalent to the MMP9 proteinase site.
Claims 75-78, 82-87, 91, 92 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 11406710 (May et al.) in view of WO200310638 (Bannen et al.), as evidenced by Gavert et al., 2007 Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis, Cancer Res, 67: 7703-7712.
As discussed above, May et al. teach a construct comprising linkers digestible by a protease that has no biological activity until it is in the presence of a protease. Upon interaction with a protease, the fragments released from the digestion result in bispecific antibodies that bind to CD3+ cells and cancer cells.
While May et al. teach digestion sites for MMP2/9, they do not teach SEQ ID NO: 196.
Bannen et al. teach instant case’s SEQ ID NO: 201, see Bannen et al. page 46, top. Bannen et al., Example 5, teach that this sequence is an ADAM10 digestion site. Bannen et al. also teach that ADAM10 is found at the site of cancer. See also Gavert et al. who teach that ADAM10 localizes at the cancer site (Gavert et al., Title).
One would have substituted Bannan et al.’s ADAM10 digest site with May et al.’s cleavable linker. One would have done so because both Bannan et al. and May et al. teach peptides that can be digested by proteases. There would have been reasonable expectation of success that Bannan et al.’s site would have worked in May et al.’s system as Bannan et al. show that instant case’s SEQ ID NO: 201 is a digest site.
Claims 75, 76, 80-82, 87, 89-92, 97 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 10822419 (Wang et al.) in view of WO200310638 (Bannen et al.), as evidenced by Gavert et al., 2007 Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis, Cancer Res, 67: 7703-7712.
As discussed above, Wang et al. teach CAR T cells that comprise a CAR construct connected to a masking peptide by a linker cleavable by a protease.
While Wang et al. teach a cleavable linker, they do not specifically teach SEQ ID NO: 196.
Bannen et al. teach instant case’s SEQ ID NO: 201, see Bannen et al. page 46, top. Bannen et al., Example 5, teach that this sequence is an ADAM10 digestion site. Bannen et al. also teach that ADAM10 is found at the site of cancer. See also Gavert et al. who teach that ADAM10 localizes at the cancer site (Gavert et al., Title).
One would have substituted Bannan et al.’s ADAM10 digest site with Wang et al.’s cleavable linker. One would have done so because both Bannan et al. and Wang et al. teach peptides that can be digested by proteases. There would have been reasonable expectation of success that Bannan et al.’s site would have worked in Wang et al.’s system as Bannan et al. show that instant case’s SEQ ID NO: 201 is a digest site.
Claims 75, 76, 79, 87, 88, 92, 97 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 8734774 (Frelinger et al.) in view of WO200310638 (Bannen et al.), as evidenced by Gavert et al., 2007 Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis, Cancer Res, 67: 7703-7712.
As discussed above, Frelinger teach chimeric fusion proteins of IL-2 connected to Mip1alpha by a linker cleavable by a protease.
While Frelinger et al. teach the use of PSA proteinase site that was used to connect IL-2 and Mip1alpha, they do not teach an ADAM10 cleavage site.
Bannen et al. teach instant case’s SEQ ID NO: 201, see Bannen et al. page 46, top. Bannen et al., Example 5, teach that this sequence is an ADAM10 digestion site. Bannen et al. also teach that ADAM10 is found at the site of cancer. See also Gavert et al. who teach that ADAM10 localizes at the cancer site (Gavert et al., Title).
One would have substituted Bannan et al.’s ADAM10 digest site with Frelinger et al.’s cleavable linker. One would have done so because both Bannan et al. and Frelinger et al. teach peptides that can be digested by proteases. There would have been reasonable expectation of success that Bannan et al.’s site would have worked in Frelinger et al.’s system as Bannan et al. show that instant case’s SEQ ID NO: 201 is a digest site.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 75-97 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11739132 (‘132). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are drawn to linkers that comprise protease targets, wherein the sequences are SEQ ID NOs: 195-198, 200. The linkers connect proteins to a steric blocking moiety. Upon contact with a protease, the protein separates from the steric blocking moiety and becomes biologically active. ‘132 is a species of the instant case, as the claims are drawn only to SEQ ID NO: 198. ‘132 anticipates the instant claims. "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus. In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989).
Claims 75-93, 95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 75-85 of copending Application No. 18315927 (‘927)(reference application), as evidenced by US Patent 5683912 (Elgoyhen et al.). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter of claims 75-93, 95 of the instant case and claims 75-85 of ‘927 overlap as being drawn to fusion polypeptides comprising a protein, a moiety that blocks the protein’s activity, and a linker comprising a protease site that connects the protein with the moiety. Upon contact with a protease, the protein separates from the moiety and becomes active. Both sets of claims recite SEQ ID NOs: 198, 199.
The claims differ from each other in that the instant claims are drawn to a protein, while ‘927 are drawn to nucleic acids encoding the protein. It is noted that at the time of filing, the art teaches that it was known that nucleic acids are translated to produce protein (Elgoyhen et al., col. 14, lines 33-36).
Regarding claim 77 ‘927, of it is noted that SEQ ID NO: 198 has the sequence ALFKSSFP.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 10/26/2023, regarding double patenting, have been fully considered but they are not persuasive. Applicant indicates that a TD has been filed for patent 11739132. However, no TD has been provided with applicant’s response of 10/26/2023. Thus, the rejection remains.
Conclusion
No claims allowed.
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/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647