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 .
Claim Rejections - 35 USC § 112
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.
Claims 1-33 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.
Claim 1, penultimate line, reads “DNA fragments polynucleotides”. This should simply read “DNA polynucleotides”, referring to the polynucleotides generated in step b. There is no mention of any fragmenting step, or other antecedent basis for “fragments”. Appropriate correction is required. Claims 2-33 ultimately depend from claim 1 and are rejected for the same reason.
In addition, claim 13 refers to “the set of DNA fragments”. This should read “the set of DNA polynucleotides” for the reasons discussed above.
Claims 1-33 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.
Claim 1 recites (in the first section of step a) “a plurality of short oligonucleotides of 8-25 nucleotides in length”, which would ordinarily be understood to mean that all the short oligonucleotides in the plurality are between 8 and 25 nucleotides (inclusive) in length. However, in the second section of claim 1, the claim recites “at least 50% of the short oligonucleotides in the plurality are 8-25 nucleotides in length”. This creates confusion, as it cannot be understood whether this supersedes the previous limitation. In any event, the two limitations seem incompatible and appropriate clarification is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 5, from which claim 6 depends, recites “wherein the DNA ligase is a thermostable ligase”. Claim 6 then recites “wherein the DNA ligase is T4 DNA ligase or Taq ligase”. T4 DNA ligase is not thermostable. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 18 and 20 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 18 and 20 ultimately depend from claim 1, which requires “a plurality of short oligonucleotides 8-25 nucleotides in length”. However, claims 18 and 20 each recite “6-18 nucleotides in length”, which does not fall within the range of 8-25. It is supposed that perhaps Applicant intended “16-18”, as is seen in claim 19.
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.
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.
Claims 1-3, 5, 7-11, 13-24 and 26-33 are rejected under 35 U.S.C. 103 as being unpatentable over Au et al (BBRC 248:200-203 (1998)) in view of Dunn et al (Analytical Biochemistry 228:91-100 (1995)).
Regarding claim 1, Au taught A method of assembling a DNA molecule having a desired sequence
Page 200, right column, last paragraph preceding “Materials and Methods”: “This paper described the synthesis of a leptin-L54 gene by a LCR-based method…”.
comprising: a) contacting a DNA ligase with a plurality of short oligonucleotides comprising at least a portion of the desired sequence of the DNA molecule to be assembled to create a mixture,
Page 200, last paragraph carrying over: “Fifty microliters of reaction mixture contained 2.2 µM of each ODN (A1-A9 or B1-B9), 8 units Pfu DNA ligase…”.
wherein at least a portion of the short oligonucleotides in the plurality overlap with and are complementary to a portion of the sequence of at least one other short oligonucleotide in the plurality, and wherein at least two of the short oligos abut one another when bound to their complementary sequence(s)
See Fig. 1 which shows the overlapping and abutting nature of the oligos to assemble each of fragments A and B. In addition, one of ordinary skill in the art would have understood the oligos were abutting since the LCR reaction contained no polymerase. Therefore, if the oligos were not abutting, they could not have been joined by DNA ligase, and the method would not have worked.
b) performing a ligase chain reaction on the mixture to thereby generate a set of polynucleotides,
See page 201, first three lines, and see Fig. 1.
and c) contacting the set of polynucleotides with a DNA polymerase and dNTPs to join the set of DNA polynucleotides, and to thereby assemble the DNA molecule having the desired sequence
See page 201, first full paragraph: “After LCR, reaction mixture of fragment A and B were pooled…10 µl of the pooled mixture was aliquoted in 100 µl fusion solution containing 0.2 mM dNTP, 2 units Vent DNA polymerase…”. See also Fig. 1.
Regarding claims 2 and 3, see Fig. 1: “After LCR, fragments A and B with 23-bp overlap were fused by cycles of denaturation, mutual priming, and extension reaction.”
Regarding claim 5, Pfu DNA ligase is thermostable.
Regarding claim 7, see page 200, last paragraph: “All the ODNs except A1, A9, B1 and B9 were 5’-phosphorylated.” In addition, one of ordinary skill would have understood the 3’ ends of the oligos bore 3’ hydroxyls since the ligations would not have worked otherwise.
Regarding claim 8, see Fig. 1: “Finally, the full-length synthetic gene was amplified by PCR using 5’- and 3’-end primers.”
Regarding claim 9, Au’s method was performed in solution (i.e. none of the oligos or intermediate products were indicated as being immobilized to a solid phase).
Regarding claims 10 and 11, Au’s sequence was 441 bp (see page 201, left column, last paragraph).
Regarding claim 13, the term “PCA” does not distinguish over the “fusion” of Au’s fragment A and B:
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Regarding claim 14, Au carried out 15 cycles of PCR; page 201, left column, first full paragraph.
Regarding claims 15 and 17, Au’s method involved 18 oligos (9 for each of fragments A and B; see Fig. 1).
Regarding claim 21, Au’s method did not require use of a restriction enzyme for assembling the desired sequence.
Regarding claim 24, Au’s method did not utilize “error correction enzymes”.
Regarding claim 26, Au’s method was performed in vitro.
Regarding claim 28, Au’s method was scarless (i.e. it did not leave intervening linkers or sequences between segments of the desired sequence).
Regarding claim 30, Au’s method did not utilize linkers, adaptors, or spacers.
Regarding claim 31, Au conducted 15 cycles of LCR (page 201, first three lines).
Au did not use short oligos where the length was 8-25 nucleotides, as recited in claim 1.
Au did not use at least 20 oligos as recited in claim 16.
Au did not use oligonucleotides within the size ranges recited in claims 18-20.
Regarding claims 22 and 23, Au did not demonstrate an error rate as recited in the claims.
Regarding claim 27, Au did not use oligos that were 8-mers or 16-mers (the shortest used were 20-mers; page 200, last paragraph).
Au did not use more than 64 oligos as recited in claim 29.
Au did not use oligos such that less than 10% or less than 1% were longer than 22 nucleotides as recited in claims 32 and 33.
Regarding the length of the oligonucleotides, Au states (page 200, right column, first paragraph): “The inborn mutation rate per nucleotide of long ODNs is thus significantly higher than that of short ODNs.”
Thus, Au disclosed a results-effective variable in that synthesis of shorter oligos results in fewer mutations than synthesis of longer oligos, which provides a motivation for using shorter oligos.
Dunn disclosed the ligation of oligos of only 6 nucleotides in length, using complementary ligation templates of the same size (see title, figure 1).
It would have been prima facie obvious to one ordinary skill in the art prior to the effective filing date of the instant application to reduce the size of the oligos when practicing the method of Au, since Au taught that shorter oligos produce fewer mutations. Dunn provides a reasonable expectation of success that the oligos could be reduced to as small as 6 nucleotides, and still be assembled into desired longer sequences. Thus, oligos ranging in size from 6 nucleotides up to the size Au used would have been prima facie obvious (MPEP 2144.05-I). In doing so, one would have arrived at the claimed invention by arriving at the smaller oligos recited in the claims, as well as the resulting lower error rates. In addition, by reducing the size of the oligonucleotides, one would have required more oligos to synthesize the same desired sequence (e.g. a 441 bp product broken up into 6 nucleotide oligos would require about 73 oligos per strand (i.e. upper and lower strands), thus arriving at the “at least 20” oligos recited in claim 16 and “more than 64” recited in claim 29.
Claims 4 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Au et al (BBRC 248:200-203 (1998)) in view of Dunn et al (Analytical Biochemistry 228:91-100 (1995)) as applied to claims 1-3, 5, 7-11, 13-24, and 26-33 above, and further in view of Chalmers et al (BioTechniques 30:249-252 (2001)).
The disclosures of Au and Dunn have been discussed. While Au taught phosphorylation of the oligos (see discussion of claim 7 above), Au did not disclose contacting the oligos with a kinase, as recited in claim 14. Au did not use 15 pools of oligos as recited in claim 25 (Au used only two).
Chalmers disclosed a “scaling up” of the method of Au (see Fig. 1).
Regarding phosphorylation of oligos, Chalmers disclosed this involved contacting the oligos with kinase (see page 294, right column, “1. Phosphorylation of Oligonucleotides in Sets of 14”).
Regarding the use of 15 pools of oligos, Chalmers used only 6 pools (see e.g. Figure 1 at top). However, the use of 15 pools represents either a mere scaling up to synthesize more segments for making larger and larger desired sequences. In addition, as discussed in the rejection of claim 1, there was a reason to reduce the size of the oligos, in that shorter oligos result in fewer errors during oligo synthesis. Therefore, reducing the size of the oligos would result in a requirement for more oligos to assemble the same sequence. Chalmers noted that LCR became inefficient when more than 14 oligos were combined in one reaction (page 249, right column, first full paragraph). By reducing the size of the oligos, and adhering to combining no more than 14 oligos per LCR reaction, one would necessarily have had to use more pools, thereby providing a reason to arrive at 15 pools of oligos (or more).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to use kinase to phosphorylate the oligos when practicing the method suggested by the combined disclosures of Au and Dunn, since Chalmers taught this was how oligos are phosphorylated. It would also have been obvious to arrive at 15 or more pools of oligos for the reasons discussed above.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Au et al (BBRC 248:200-203 (1998)) in view of Dunn et al (Analytical Biochemistry 228:91-100 (1995)) as applied to claims 1-3, 5, 7-11, 13-24, and 26-33 above, and further in view of Graham (US 2002/0168341).
The disclosures of Au and Dunn have been discussed. Au did not use Taq DNA ligase, but rather Pfu DNA ligase.
Graham disclosed Taq ligase for performing LCR (paragraph [0070]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the Pfu ligase used by Au with Taq ligase as taught by Graham, as both were known for use in conducting LCR (MPEP 2144.06).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Au et al (BBRC 248:200-203 (1998)) in view of Dunn et al (Analytical Biochemistry 228:91-100 (1995)) as applied to claims 1-3, 5, 7-11, 13-24, and 26-33 above, and further in view of Rinehart (US 2019/0256843).
The disclosures of Au and Dunn have been discussed. Au did not incorporate universal sequences into the synthesized sequence.
Rinehart disclosed methods of gene synthesis (paragraph [0089]) in which “one set of 20 bp universal primer annealing sequences was encoded in every DNA sequence at the 5’ and 3’ termini”.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to incorporate universal sequences in to the end of the synthesized sequence when practicing the method of Au, so that multiple sequences of interest could be synthesized by the LCR/fusion steps, and all such sequences could be amplified (at the PCR step) using the same pair of primers.
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 1-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12,018,316. Although the claims at issue are not identical, they are not patentably distinct from each other because the essential difference in scope between the issued claims and the instant claims is that the former additionally requires that the reaction is performed in one step. Therefore, the issued claims represent a narrower species that anticipates the instant generic claims, rendering them obvious.
Conclusion
No claims are free of the prior art.
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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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