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 .
1. Formal Matters
A. Applicant’s election without traverse of Group I, drawn to the indicated species, in the reply filed on 12/18/25 is acknowledged. Therefore, the restriction dated 10/20/25 is proper and is therefore made FINAL. However, upon further review all species have been examined.
B. Claims 1-12 and 14-20 are pending. Claims 14 and 16 are withdrawn as being drawn to a non-elected invention. Claims 1-12, 15 and 17-20 are the subject of this Office Action.
2. 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.
Claim 1-8, 11, 12 and 15 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.
The claims are broadly drawn to antibodies comprising “an antibody fragment derived from the antibody”. Thus, the claims encompass antibodies that comprise one or more alterations to one or more of the 6 CDRs.
Paragraph [0148] of the published application defines “an antibody fragment derived from the antibody” as –
Such an antibody fragment is intended to mean a partial region of the anti-hDLK-1 polyclonal antibody or the anti-hDLK-1 monoclonal antibody (i.e., an antibody fragment derived from the anti-hDLK-1 antibody of the present invention), and examples include Fab, Fab′, F(ab′)2, Fv (variable fragment of antibody), single chain antibody (e.g., H chain, L chain, H chain V region, and L chain V region), scFv, diabody (scFv dimer), dsFv (disulfide stabilized V region), as well as peptides at least partially containing complementarity determining regions (CDRs), etc.
The issue lies in the last limitation of the definition, which refers to “peptides at least partially containing complementarity determining regions (CDRs), etc.” Therefore, these claims read on pharmaceutical compositions comprising antibody fragments with fewer than all 6 CDRs and the specification only teaches that antibodies which specifically bind to human DLK-1 comprise all 6 CDRs of those known in the prior art, including those with SEQ ID NOs recited in instant claims 10 and 17-20. The term “etc.” makes the definition even more vague.
The nature of the invention is engineered antibodies where the relative level of skill of those in the art is deemed to be high. The state of the prior art is such that it is well-established in the art that the formation of an intact antigen-binding site of antibodies routinely requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, William E., Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapt. 8, pp. 292-295 (1993), under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman P. M. (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3).
Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3). While there are some publications which acknowledge that CDR3 is important, the conformations of other CDRs as well as framework residues influence binding. MacCallum et al (J. Mol. Biol., 262, 732-745, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col.) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
Further, Chen et al. (EMBO J., 14: 2784-2794, 1995) teach that the substitution of a single amino acid can totally ablate antigen and that the same substitution in closely related antibodies can have opposite effects binding (e.g., see entire document, including Figure I). For example, the authors compared the effects of identical substitutions in related antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. As such, it is unpredictable which combination of random substitution has the recited function.
Thus, the state of the art recognized that it would be highly unpredictable that a specific binding member comprising an antibody comprising one or more substitutions to one or more of the six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification and prior art, limited to antibody fragments that comprise all 6 wild-type CDRs of the known/disclosed antibodies to those that comprise alterations in one or more CDRs from the parental antibodies.
In summary, in view of the lack of the predictability of the art to which the invention pertains as evidenced by the above references, the lack of guidance and direction provided by applicant, and the absence of working examples, the Examiner concludes that undue experimentation would be required to practice the invention as claimed.
3. 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 (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 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.
A. Claims 1-5, 7-12, 15, 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bartz et al. in view of Xie et al. (U.S. Patent No. 8,017,118. It is noted that the first inventor listed on the patent as cited in the attached PTO-892 is Nakamura, though Xie is cited in the sequence comparison below).
Claims 1-5 are drawn to pharmaceutical compositions comprising an FGFR4 inhibitor and an anti-human DLK-1 antibody.
Bartz teaches an FGFR4 antibody for the treatment of liver cancer (entire document), and that aberrant FGFR4 signaling is seen in breast and colon cancer, and is a cancer driver in hepatocellular carcinoma (first sentence on page 1833; see instant claim 8). The antibodies of Bartz were tested in vivo, meeting the limitation of a pharmaceutical composition. These antibodies bind to FGFR4 expressed on liver cells, meeting claims 7 and 8. Bartz does not anti-hDLK-1 antibodies. However, Xie does teach those identical to instant SEQ ID NO:16 and 18 in claims 10 and 17-20. Xie also teaches a kit for treatment (column 5, lines 26-30). Claim 11 is met by Figure 13 of Xie, which conjugates the antibody to the toxin saporin. Claim 12 is met by, e.g. Figure 15. Claim 9 is met by Figure 25, which teaches both chimeric and humanized antibody expression vectors.
In re Kerkhoven (205 USPQ 1069, CCPA 1980) summarizes:
"It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for the same purpose in order to form a combination that is to be used for the very same purpose: the idea of combining them flows logically from their having been individually taught in the prior art."
SEQ ID NO:16
Patent No. 8017118
GENERAL INFORMATION
APPLICANT: Xie, Wenge
APPLICANT: Tajima, Rie
APPLICANT: Kumar, Shankar
APPLICANT: Tso, Yun J.
APPLICANT: Tsurushita, Naoya
TITLE OF INVENTION: ANTI-HDLK-1 ANTIBODY HAVING AN ANTITUMOR ACTIVITY IN VIVO
FILE REFERENCE: 09857/1209358-US1
CURRENT APPLICATION NUMBER: US/12/404,419
CURRENT FILING DATE: 2009-03-16
PRIOR APPLICATION NUMBER: US 61/069,834
PRIOR FILING DATE: 2008-03-17
NUMBER OF SEQ ID NOS: 84
SEQ ID NO 23
LENGTH: 137
TYPE: PRT
ORGANISM: Mus musculus
Query Match 100.0%; Score 624; Length 137;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLQQSGAELVKPGASVKLSCTASGFNIRDTYIHWVKQRPEQGLEWIGRIDPPNGNLKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 20 EVQLQQSGAELVKPGASVKLSCTASGFNIRDTYIHWVKQRPEQGLEWIGRIDPPNGNLKY 79
Qy 61 DPKFQGKATITADTSSNTAYLQFSSLTSEDTAVYYCARSDGYSFAYWGQGTLVTVSAA 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 80 DPKFQGKATITADTSSNTAYLQFSSLTSEDTAVYYCARSDGYSFAYWGQGTLVTVSAA 137
SEQ ID NO:18
SEQ ID NO 70
LENGTH: 112
TYPE: PRT
ORGANISM: Mus musculus
Query Match 100.0%; Score 583; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVMTQAAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRMSNLA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVMTQAAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRMSNLA 60
Qy 61 SGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHVEYPFTFGSGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHVEYPFTFGSGTKLEIK 112
B. Claims 1-12, 15, 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al. (U.S. Patent No. 8,017,118) in view of Weiss et al.
The teachings of Xie are seen above in paragraph A of this section. Xie does not teach FGF401 (claim 6). However, Weiss teaches FGF401 is an FGFR4 inhibitor for the treatment of hepatocellular carcinoma (entire document). See also In re Kerkhoven (205 USPQ 1069, CCPA 1980).
C. Claims 1-12, 15, 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al. (U.S. Patent No. 8,017,118) in view of Joshi et al.
The teachings of Xie are seen above in paragraph A of this section. Xie does not teach H3B-6527 (claim 6). However, Joshi teaches H3B-6527 is an FGFR4 inhibitor for the treatment of hepatocellular carcinoma (entire document). See also In re Kerkhoven (205 USPQ 1069, CCPA 1980).
D. Claims 1-12, 15, 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al. (U.S. Patent No. 8,017,118) in view of Kim et al.
The teachings of Xie are seen above in paragraph A of this section. Xie does not teach BLU-554 (claim 6). However, Kim teaches BLU-554 is an FGFR4 inhibitor for the treatment of hepatocellular carcinoma (entire document). See also In re Kerkhoven (205 USPQ 1069, CCPA 1980).
E. Claims 1-5, 7-12, 15, 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al. (U.S. Patent No. 8,017,118) in view of Kanzaki et al.
The teachings of Xie are seen above in paragraph A of this section. Xie does not teach an FGFR4 inhibitor. However, Kanzaki teaches the FGFR4 inhibitor lenvatinib for the treatment of hepatocellular carcinoma (entire document). See also In re Kerkhoven (205 USPQ 1069, CCPA 1980).
4. Nonstatutory 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 1-5, 7-12, 15 and 17-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6 and 9 of copending Application No. 17/599,820 (reference application) in view of Kanzaki et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to essentially the same subject matter. Instant SEQ ID NO:36 and 46 are identical to SEQ ID NO:36 and 46 of the copending application. The only difference is that the instant claims do not recite lenvatinib. However, Kanzani teaches that Lenvatinib targets FGF4 in HCC (entire document).
Claim 1 of the copending application teaches a pharmaceutical composition comprising lenvatinib and the DLK-1 antibody identical to SEQ ID NO:36 and 46, meeting instant claims 1-5, 10 and 17-20.
Claim 2 of the copending application meet instant claim 7 and 8. Claim 3 meets claim 9. Claim 5 meets claim 11. Claim 6 meets claim 12. Claim 9 meets claim 15.
In the interest of compact prosecution, if instant claims 14 and 16 are rejoined, copending claim 8 would meet these methods of treating.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
5. Conclusion
No claim is allowable.
Advisory information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT S LANDSMAN whose telephone number is 571-272-0888. The examiner can normally be reached M-F 8 AM – 6 PM (eastern).
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/ROBERT S LANDSMAN/Primary Examiner, Art Unit 1647