Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Responsive to communications entered 7MAR2026
Claims Pending 1-17,20-22
Claims Under Consideration 1-17,20-22
Priority
This application has a filing date of 06/21/2022 and is a CON of
16/749,643 01/22/2020 PAT 11396556
16/749,643 is a CON of 15/593,721 05/12/2017 PAT 10562981
15/593,721 is a CON of 13/977,166 06/28/2013 PAT 9683054
13/977,166 is a 371 of PCT/US2011/067589 12/28/2011
PCT/US2011/067589 has PRO 61/428,917 12/31/2010
Maintained Claim Rejection(s) - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-12,17,20-22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Frey et al II (WO 2008/079466) in view of Frey et al III (US AppPub 20050130156).
Like claims 1(other than evolution of parts a and b),2,3,4,5,6,7,8,9,11 (when drawn to reduced immunogenicity),12,17, Frey et al II teach throughout the document and especially the abstract and figure 1, humanizing antibodies or fragments thereof by grafting murine CDRs (complementarity determining regions) into human frameworks. More particularly at p 3 line 8 to p 4 line 19; p 7; and the tables, Frey et al II:
synthesizes immunoglobulin heavy chain double stranded DNA fragment libraries comprising complementarity determining region fragment encoding segments and framework fragment encoding libraries, wherein at least one complementarity determining region includes at least one double stranded DNA fragment encoding at least a portion of a heavy chain complementarity determining region having sequence identity to a complementarity determining region of a mouse template antibody and each framework fragment library includes at least one double stranded DNA fragment encoding a portion of a heavy chain framework necessarily from a human framework pool obtained from functionally expressed human antibodies having framework regions that have a sequence identity with a framework region of the template antibody (in so far as heavy chain framework 4 is, for example, WG or else heavy chain framework 1 comprises VQ, at least that are conserved in mice and humans);
synthesizes an immunoglobulin light chain double stranded DNA fragment libraries comprising complementarity determining region fragment encoding segments and framework fragment encoding libraries, wherein at least one complementarity determining region includes at least one double strand fragment encoding at least a portion of a light chain complementarity determining region having sequence identity to a complementarity determining region of the template antibody and each framework fragment library comprising at least one double stranded DNA fragment encoding a portion of a light chain framework necessarily from a human framework pool obtained from functionally expressed human antibodies having framework regions that have a sequence identity 100% with a framework region of the template antibody (in so far as light chain framework 3 has, for example, a SG sequence at least that is conserved in mice and humans); and
assembles from the heavy and light chain fragment libraries by joining heavy and light chain framework encoding fragments from the heavy and light chain framework fragment encoding libraries and heavy and light chain complementarity determining regions in the order of: framework1 - complementarity determining region1 - framework2 - complementarity determining region2 - framework3 - complementarity determining region3 and optionally framework4.
And at p 11 lines 10-12; p 47 lines 20-24, the paragraph spanning pp 47-48 and p 12 lines 6-15, Frey et al II further suggest: cloning (with a ligation step occurring endogenously) such assembled humanized heavy chain variable domain encoding library and the assembled light chain variable domain encoding library into an expression vector to create a humanization library; transfecting the humanization library into, for example, CHO cells; expressing humanized antibodies or humanized antibody fragments in the cells to create a humanized antibody library with fewer than 100,000 members; and finally screening the humanized antibody library to determine an affinity of the humanized antibodies or humanized antibody fragments for an antigen compared to an affinity of the template antibody to the same antigen such as via ELISA.
Frey et al II do not teach: using either substitutions, insertions and deletions; nor comprehensive positional evolution to evolve at least a portion of such mouse complementarity determining regions (CDRs) to provide modified heavy and light chain CDRs of claim 1(a & b),20,21; nor heavy and light chains expressed from a single promoter as recited in claim 10.
Frey et al III suggest throughout the document and especially paragraphs 0110, 0234,0236,0079 and figures 2-5 stepwise synthetic ligation reassembly in concert with point mutations introduced by saturation mutagenesis and/or CDR shuffling in an effort to evolve a part or an entire CDR(s) in single chain antibodies derived from a mouse (having heavy and light chains expressed in one transcript). In other words, as defined in paragraph 0049 of the present published application, using comprehensive positional evolution Frey et al III evolves at least a portion of mouse CDRs to provide modified heavy and light chain CDRs with heavy and light chains expressed from a single promoter as in claims 1(a & b), 10 and 21. And like claim 20, said CDR shuffling is inherently accomplished by substitutions, insertions and deletions, whereas as in claims 1(a & b) and 22, saturation mutagenesis to introduce CDR single point mutations necessarily have at least 90% sequence identity to, for instance CDR1H (SEQ ID 151) and CDR1L (SEQ ID 163) such as set forth in Frey et al II table 6.
It would have been prima facie obvious for one of ordinary skill in the art, at the time the claimed invention was made to have employed comprehensive positional evolution technique advocated by Frey et al III to modify the mouse CDRs of Frey et al II.
One of ordinary skill in the art would have been motivated to have employed comprehensive positional evolution technique advocated by Frey et al III to modify the mouse CDRs of Frey et al II and had a reasonable expectation of success in doing since Frey et al III suggest the technique may be used to improve protein properties such as greater thermotolerance among other indeed report compelling experimental results concerning thus in paragraphs 0483-0485.
Claims 1-12,17,20-22 and 13-16 are rejected under 35 U.S.C. 103(a) as being unpatentable over Frey et al II (WO 2008/079466) in view of Frey et al III (US AppPub 20050130156) and further in view of in view of Nielsen et al (US 7910332; of record).
Frey et al II in view of Frey et al III is relied upon as above.
Frey et al II in view of Frey et al III do not teach: eukaryotic cell surface display of heavy and light chains such as recited in claim 15; nor CHO-S & NS0 as eukaryotic production host cells of claims 13-14 and 16.
As in claims 13,14,15,16, Nielsen et al teach throughout the document and especially the title and column 12 line 44 to column 13 line 50 and column 15, generating polyclonal antibodies (libraries) optionally in scFv format in CHO-S and NS0 cells and/or screening thus by yeast surface display. Said scFv antibodies necessarily have heavy and light chains expressed from a single promoter further reading on claim 10.
It would have been prima facie obvious for one of ordinary skill in the art, at the time the claimed invention was made to have prepared antibodies per Frey et al II in view of Frey et al III with the methods suggested by Nielsen et al.
One of ordinary skill in the art would have been motivated to have prepared antibodies per Frey et al II in view of Frey et al III with the methods suggested by Nielsen et al for the advantages of requiring fewer cultures and/or purification of every library member simultaneously, benefits noted by Nielsen et al in the paragraph spanning columns 12 to 13.
One of ordinary skill in the art would have had a reasonable expectation of success in applying the manufacturing methods of Nielsen et al toward producing antibodies as in the Frey references in so far as yeast display of scFvs; and CHO-S, NS0 as hosts all represent robust technology well recognized as robust in the art, having been used for decades.
In conclusion, the entirety of claims 1-17,20-22 are rendered obvious based on the Frey et al II, Frey et al III and Nielsen et al references.
***
Please note that the above rejection has been modified from the original version to more clearly address applicants’ concerns.
Response to Arguments
Arguing both of the above rejections together, the remarks accompanying the current response argue: (i) the first rejection above of Frey et al II (referred to as WO ‘466) in view of Frey et al III (referred to as US ’156) is improper; (ii) not all elements are taught; (iii) Frey et al III teaches away from the presently claimed subject matter; and (iv) saturation mutagenesis suggested by Frey et al III is on fully formed antibodies rather than CDRs.
Applicant’s arguments have been fully considered but they are not deemed persuasive for the following reasons.
More particularly concerning argument (i), page 7 of the remarks attacks the last action, asserting (A) US AppPub 20090285813 (Frey I) cited previously by the examiner previously is the national stage entry of WO ‘466 thus allegedly it has an identical disclosure and (B) the examiner has only evaluated claim 1 in part. In response to (A), the examiner submits WO ‘466 (Frey et al II) does indeed differ from Frey I in so far as incorporation by reference doctrine under 37 CFR 1.57(c) does not apply to international stage WIPO documents as opposed to US applications, therefore the disclosures indeed differ per se. And in response to (B), as noted in the statement of rejection copied from the previous action, as clarified and detailed above, in contrast with the arguments of counsel, claim 1 has been considered as whole and is deemed obvious over Frey et al II in view of Frey et al III based on the factors laid out by the Supreme Court in Graham v. John Deere, 383 U.S. 1, 148 USPQ 459 (1966). Consequently examiner submits the rejection was properly made.
More particularly regarding argument (ii), p 8 of the remarks contends Frey et al II does not teach evolution of claim 1 a & b; nor stepwise liquid phase ligation in the manner of claim 1 c & d.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, comprehensive positional evolution (saturation mutagenesis) is suggested by Frey et al III as detailed in the rejection supra as well as further discussed in relation to argument (iv) below.
Concerning stepwise liquid phase ligation in the order recited in claim 1 c & d, it is noted that while Frey et al II suggest joining in a 5'-to-3' orientation, nucleic acids encoding the FW1-CDR1-FW2-CDR2-FW3-CDR3 and optionally FW4 domains (VH or VL libraries), for instance on p 8 and while the page does not explicitly indicate that such joining may be performed by liquid phase ligation in paragraphs 0241-0242 of the present published application, applicant admits liquid phase stepwise ligation of such VH or VL libraries libraries may be performed by techniques known to one of skill in the art.
In reference to argument (iii) set forth in the third paragraph at p 9 of the remarks urging Frey et al III teaches away from liquid phase rather than solid-phase ligation such as illustrated in figure 1, as interpreted in MPEP 2123 II, the courts have held disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiment and "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Here, nowhere does Frey et al III disparage solution phase ligation in any way and indeed suggests it in figures 2-5.
Lastly concerning argument (iv) that Frey et al III performs saturation mutagenesis (comprehensive positional evolution) on fully formed antibodies as opposed to CDRs before assembly, as interpreted in MPEP 2144.04 IV under In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) the court held selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. As such, absent evidence to the contrary, performing saturation mutagenesis during assembly would not provide antibodies with surprising properties.
Applicant does not proffer any further arguments regarding the second obviousness rejection including Nielsen et al beyond what was set forth with regard to the first based on Frey et al II in view of Frey et al III alone. To the extent that Applicant is merely repeating their previous argument, the examiner respectfully submits that those issues were adequately addressed in the above section(s), which is/are incorporated in their entireties herein by reference.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTOPHER M GROSS whose telephone number is (571)272-4446. The examiner can normally be reached M-F 10-6.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571)272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTOPHER M GROSS/Primary Examiner, Art Unit 1684
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