Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
2. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 1, 2, 6, 10-12, 28, 42, 43, 47, 51-53, 69, 83, 84, 88, 92-94, 110, 124, 126, 128 and 129 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A. Regarding claim 1 in steps (a)-(d) applicant recites providing “a first polynucleotide,” “a second polynucleotide,” “a first vector polynucleotide,” and “a second vector polynucleotide.” In step (f) these four components are linked to form “first to-be-screened vectors,” but it is unclear based on the language of the claims how four individual components all linked together become multiple vectors. The same issue appears in steps (a)-(d) and step (f) of claims 42 and 83. Additionally, claim 42 recites the phrase “wherein the nucleic acid fragment II’ is capable of encoding an antigen-binding protein II’, and an antigen-binding fragment II’, together with the reference antigen-binding fragment I, is capable of forming an antigen-binding protein having the following property…” It is unclear, based on the claim language and the language of applicant’s specification (see [0075], and [00149] for example) if the nucleic acid fragment II’ is intending to be capable of encoding an entire antigen-binding protein II’, or if nucleic acid fragment II’ is intended to encode antigen-binding fragment II’ as is consistent with the language of claims 1 and 83. For these reasons, claims 1, 42 and 83 are indefinite.
B. In claim 10, the phrase “the restriction endonuclease” lacks proper antecedent basis because claim 1 is sufficiently broad to encompass cleaving each polynucleotide recited in step (e) with a different restriction endonuclease, and therefore it is unclear which endonuclease is “the restriction endonuclease” referred to by claim 10.
C. Claim 11 recites the phrase “the first to-be-screened vector,” however the antecedent basis in claim 1 is “the first to-be-screened vectors.” Therefore this claim is indefinite because is not clear which of the vectors in claim 1 is “the” vector referred to in claim 11. The same issue is repeated in claims 52 (with antecedent basis to claim 42) and 92 (with antecedent basis to claim 83). Therefore these claims are indefinite.
D. Claim 124 recites the phrase “the antigen-binding protein comprises…” however claim 1, upon which claim 124 depends, recites two antigen-binding proteins: a reference antigen-binding protein and a functional antigen binding-protein. Claim 124 does not have proper antecedent basis to either of these recitations and therefore it is indefinite.
E. All other claims rejected by not specifically mentioned here are rejected due to being dependent on a previously rejected claim.
Claim Rejections - 35 USC § 103
4. 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.
5. Claims 1, 2, 6, 10-12, 28, 42, 43, 47, 51-53, 69, 124, 126, 128 and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (Four-way ligation for construction of a mammalian cell-based full-length antibody display library, Acta Biochim Biophys Sin, 43, 232-238, published 21 January 2011; hereinafter referred to as ZhouA) in view of Zhou et al (Development of a novel mammalian cell surface antibody display platform, mAbs, 2, 5, 508-518, published 01 September 2010; hereinafter referred to as ZhouB).
Regarding claim 1 and 129, ZhouA teaches a method for preparing human antibody libraries comprising a PCR product comprising an antibody heavy chain (HC, pg. 233 column 1 ¶ 5 and Table 1; an antigen binding fragment, although it is noted here that any nucleic acid sequence of sufficient length is capable of encoding an antigen binding fragment and the claim language does not explicitly require that it does encode such a fragment) sequence flanked by a BstXI restriction site at either end (i.e., R1-nucleic acid fragment I-R2; wherein R1 is the forward BstXI restriction site, nucleic acid fragment I is the HC sequence and R2 is the reverse BstXI restriction site). Zhou A further teaches providing a second PCR product comprising a light chain sequence (LC, pg. 233 column 1 ¶ 5 and Table 1; an antigen binding fragment) flanked by an SfiI restriction site at each end (i.e., R3 and R4), and a third and fourth PCR products comprising frame sequences flanked by restriction enzyme sites (i.e., vector fragments 1 and 2; pg. 233 column 1 ¶ 5 and Table 1). ZhouA further teaches that the LC and HC fragments are amplified from a library of human kappa chain sequences or HC variable domain sequence (pg. 235 column 2 ¶ 2), and as such either sequence meets the criteria in claim 1 of “being capable of encoding a reference antigen-binding fragment II, which, together with a reference antigen-binding fragment I encoded by a reference nucleic acid fragment I, is capable of forming a reference antigen-binding protein.” It is noted that a kappa chain (e.g., an LC) or HC library from a human encodes for an antigen binding fragment II (e.g., a light chain fragment) that with an antigen binding fragment I (e.g., a heavy chain fragment) is capable of forming an antibody (e.g., a reference antigen binding protein). It is further noted that the claim, as written, only requires that the reference nucleic acid fragment II is capable of encoding a reference antigen binding fragment II which is further only capable of forming an antigen-binding protein with a reference antigen-binding fragment I. Any nucleic acid fragment of specific length is capable of encoding such a fragment, and whether or not it does is not required by the claim as written.
ZhouA teaches that all four of these fragments are cleaved with restriction endonucleases to provide cleaved products (pg. 233 column 1 ¶ 5), and that the products are mixed and cyclized by ligation to produce vectors for screening (pg. 233 column 2 ¶ 1). ZhouA teaches that the vectors were transformed into mammalian cells and screened for antibody expression on the cell surface (pg. 233 column 2 ¶ 1 and 2).
ZhouA does not specifically teach that a ‘first to-be-screened vector’ is selected as a replacement vector based on it’s capability of binding to a target, to which the reference antigen-binding protein can bind, at a capacity that is 30% or more of a binding capacity of the reference antigen-binding protein to the target, nor does ZhouA teach deriving the first antigen binding protein from the first replacement vector.
However, ZhouB teaches a method of screening a mammalian display platform (abstract) comprising a variable HC fragment (any one of which would correspond to nucleic acid fragment I of instant claim 1; FIG 7) expressed with a constant LC fragment (i.e., the claimed reference nucleic acid fragment; pg. 512 column 1 ¶ 2). ZhouB teaches screening these constructs via display on a cell surface and identifying constructs with comparable binding affinity than their native counterparts (i.e., can bind at a capacity that is 30% or more of the reference antigen binding protein; pg. 513 column 1 ¶ 1 and Table 2).
It would have been obvious to one having ordinary skill in the art to have modified the antibody display method taught by ZhouA with the HC modification and selection taught by ZhouB to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to change one of the antigen-binding fragments (e.g., the heavy chain) while keeping the other constant (e.g., the light chain) because ZhouB specifically teaches that the number of mutations in a library directly influences library diversity and the number of clones needed to screen a library (pg. 512 column 1 ¶ 2). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the formation and expression of antibody display libraries.
Regarding claim 2, it is first noted that this claim is being interpreted as though the phrase “a restriction endonuclease specifically recognizing R1 and R2” is intended to mean “a restriction endonuclease specifically recognizing R1 and [a restriction endonuclease specifically recognizing] R2.” This may be the same restriction endonuclease or different restriction endonucleases, based on interpretation of the applicant’s specification [00167]. The same consideration is made for R3 and R4, R2 and R3, and R4 and R1. ZhouA teaches that the HC fragment (i.e., the first polynucleotide) is cleaved by BstXI at sites R1 and R2, the LC fragment (i.e., the second polynucleotide) is cleaved by SfiI at sites R3 and R4, the short frame fragment (i.e., the first vector polynucleotide) is cleaved by BstXI at R2 and SfiI at R3, and the large frame fragment (i.e., the second vector fragment) is cleaved by SfiI at R4 and BstXI at R1 (FIG 1 and Table 1).
Regarding claim 6, ZhouA teaches that the restriction endonucleases used cleave non-palindromic sequence, that self-ligation is impossible, and that the individual border of every fragment is unique and can only bind to is complementary border during ligation (i.e., the terminus of cleaved R1 cannot recognize or link to the cleaved termini of any of R2, R3 or R4 and so on; pg. 238 column 1 ¶ 1).
Regarding claim 10, as discussed above the antecedent basis of “the restriction endonuclease” is “a restriction endonuclease” in claim 1, and this has been interpreted in light of applicant’s specification to not require that all the fragments of claim 1 are cleaved by the same restriction endonuclease (see at least [00167] and [00367] of applicant’s specification). Therefore, this claim is being interpreted as though at least one of the restriction endonucleases in claim 1 is selected from the group consisting of SfiI and BsmBI. ZhouA teaches that R1 and R2 are cleaved by SfiI (FIG 1 and Table 1).
Regarding claim 11, ZhouA teaches that antibody libraries are transfected into FCHO cells and expressed on the cell surface (pg. 236 column 1 ¶ 2 and column 2 ¶ 1).
Regarding claim 12, it is noted that every selection in this claim before (and after) step (b) is linked by and/or terminology so meeting any limitation provided before or after step (b) is sufficient to make obvious this claim. ZhouA teaches that the small frame fragment “links” the HC and LC fragments together in the vector, and the large frame fragment is “derived” from a vector (pDGB4; FIG 1 and pg. 233 column 2 ¶ 4).
Regarding claim 28, it is noted that every selection in this claim before (and after) step (b) is linked by and/or terminology so meeting any limitation provided before or after step (b) is sufficient to make obvious this claim. The combination of ZhouA and ZhouB teaches that the reference nucleic acid fragment II encodes an antibody light chain and that nucleic acid fragment I encodes an antibody heavy chain, as discussed above and fully incorporated here.
Regarding claim 42, it is noted that the phrases “nucleic acid fragment I’,” “nucleic acid fragment II’,” “vector fragment III,” and “vector fragment IV” are not given limiting definitions in the claims and as such are being broadly interpreted as any nucleic acid fragment that meets the explicitly claimed limitations. For example, nucleic acid fragment I’ is considered to be any other variant of the heavy chain library taught by ZhouB (FIG 7), nucleic acid fragment II’ is considered to be any second copy of the constant light chain fragment taught by ZhouB (pg. 512 column 1 ¶ 2; it is further noted here that nucleic acid fragment II’ is partially defined in claim 83, however claim 42 is not dependent on claim 83 and therefore any limitations of claim 83 do not apply to this dependency chain), vector fragment III is considered to be an equivalent second copy of vector fragment I (this is supported in applicant’s specification [00244]), and vector fragment IV is considered to be an equivalent second copy of vector fragment II. Additional copies of the light chain fragment meet the limitations of step (b) in claim 42 because a light chain fragment paired with its cognate heavy chain fragment will form an antigen-binding protein that is equivalent to the reference antigen binding protein with an equivalent binding capacity (i.e., 30% or more of a binding capacity of the reference antigen-binding protein). As such, claim 42 is made obvious for the same reasons claim 1 is made obvious by ZhouA and ZhouB because ZhouA teaches that more than one molecule of each fragment is added to the ligation mixture (50-100 ng of total vector and insert fragments were mixed; pg. 233 column 2 ¶ 1). In the same manner, R5 and R6 are considered equivalent to R1 and R2, respectively and R7 and R8 are considered equivalent to R3 and R4, respectively.
Regarding claim 43, it is first noted that this claim is being interpreted as though the phrase “a restriction endonuclease specifically recognizing R5 and R6” is intended to mean “a restriction endonuclease specifically recognizing R5 and [a restriction endonuclease specifically recognizing] R6.” This may be the same restriction endonuclease or different restriction endonucleases, based on interpretation of the applicant’s specification [00167]. The same consideration is made for R7 and R8, R6 and R7, and R8 and R5. ZhouA teaches that the HC fragment (i.e., the first polynucleotide) is cleaved by BstXI at sites R5 and R6, the LC fragment (i.e., the second polynucleotide) is cleaved by SfiI at sites R7 and R8, the short frame fragment (i.e., the first vector polynucleotide) is cleaved by BstXI at R6 and SfiI at R7, and the large frame fragment (i.e., the second vector fragment) is cleaved by SfiI at R8 and BstXI at R5 (FIG 1 and Table 1).
Regarding claim 47, ZhouA teaches that the restriction endonucleases used cleave non-palindromic sequence, that self-ligation is impossible, and that the individual border of every fragment is unique and can only bind to is complementary border during ligation (i.e., the terminus of cleaved R5 cannot recognize or link to the cleaved termini of any of R6, R7 or R8 and so on; pg. 238 column 1 ¶ 1).
Regarding claim 51, as discussed above the antecedent basis of “the restriction endonuclease” is “a restriction endonuclease” in claim 42, and this has been interpreted in light of applicant’s specification to not require that all the fragments of claim 1 are cleaved by the same restriction endonuclease (see at least [00167] and [00367] of applicant’s specification). Therefore, this claim is being interpreted as though at least one of the restriction endonucleases in claim 42 is selected from the group consisting of SfiI and BsmBI. ZhouA teaches that R5 and R6 are cleaved by SfiI (FIG 1 and Table 1).
Regarding claim 52, ZhouA teaches that antibody libraries are transfected into FCHO cells and expressed on the cell surface (pg. 236 column 1 ¶ 2 and column 2 ¶ 1).
Regarding claim 53, it is noted that every selection in this claim before (and after) step (b) is linked by and/or terminology so meeting any single limitation provided before or after step (b) is sufficient to make obvious this claim. ZhouA teaches that the small frame fragment (i.e., vector fragment III) “links” the HC and LC fragments together in the vector, and the large frame fragment (i.e., vector fragment IV) is “derived” from a vector (pDGB4; FIG 1 and pg. 233 column 2 ¶ 4).
Regarding claim 69, it is noted that every selection in this claim before (and after) step (b) is linked by and/or terminology so meeting any limitation provided before or after step (b) is sufficient to make obvious this claim. The combination of ZhouA and ZhouB teaches that the nucleic acid fragment II’ encodes an antibody light chain and that nucleic acid fragment I’ encodes an antibody heavy chain, as discussed above and fully incorporated here.
Regarding claim 124, it is noted that the antecedent basis of “the antigen-binding protein” is unclear as described fully above and incorporated here. However, ZhouA in view of ZhouB teach a reference antigen binding protein of Mab40-L11 (pg. 512 column 1 ¶ 3, Table 1 and Table 2) and functional antigen-binding proteins derived from mutations in the HC of the parental protein (Tables 1 and 2), and that both of these antigen binding proteins comprise antibodies.
Regarding claim 126, ZhouA teaches that the directional linkage is accomplished with T4 DNA ligase (pg. 233 column 2 ¶ 1).
Regarding claim 128, ZhouA teaches a method for preparing an antigen-binding protein that is displayed on a cell surface (i.e., expressing the first replacement vector; abstract). Since the antibody is expressed and displayed on the cell surface, this method is inherently done under conditions allowing for the expression of the first replacement vector.
Conclusion
6. No claims are allowed.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-T 0800 - 1630.
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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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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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