Status of the Claims
Claims 1-9, 11, 20-21, 23-28, 41, and 57 are currently pending and examined herein.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claims 1 and 21 are objected to because of the following informalities:
Claim 1: missing article on line 16 (“comprise [a] 3’ puromycin molecule”)
Claim 1: improper subject-verb agreement on line 17 (“3’ end… are”)
Claim 21: list in step (c) is numbered incorrectly (“(v)” should be “(iv)”)
Appropriate correction is required.
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, 4, and 24 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 the limitation "the nucleotide sequence" in 1. (a) (iii). There is insufficient antecedent basis for this limitation in the claim. For the purposes of examination, this limitation will be interpreted to mean that the polypeptide-encoding nucleotide sequence is in-frame with the initiation site.
Claims 4 and 24 recite the limitation “the splint-target sequence”. There is insufficient antecedent basis for this limitation in the claim. For the purpose of examination, “the splint-target sequence” will be interpreted as referring to “a linker-target sequence” recited in claim 3 and 23.
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 28 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 28 is dependent on claim 21, which states that the cellular RNA fragments are “from a tumor”. Claim 28 then recites that the sample is “a tumor sample, a normal tissue sample, …”. As such, claim 28 does not include all the limitations of claim 21. 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.
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.
Cho et al., Somers et al., and Seligmann et al.
Claims 1-2 and 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (J. Mol. Biol. (2000), 297: 309-319) in view of Somers et al. (J. Immunol. (2002), 169(5): 2772-2780) and Seligmann et al. (DNA and Cell Biol. (2004), 23(10): 701-705).
Regarding claim 1, Cho discloses a method of enriching a library of RNA transcripts for in-frame coding regions (abstract), comprising:
joining RNA transcripts transcribed from DNA to 3’ puromycin-tagged linker polynucleotides, where the 3’ end of the RNA is joined to the 5’ end of the puromycin-tagged polynucleotides (p. 310, General Strategy: "RNA is generated from the DNA library and then modified at the 3’ end to add a short DNA segment that is terminated with puromycin”), wherein:
the RNA transcripts each comprise, in 5’ to 3’ order:
a translation initiation site (Figure 1: AUG) in frame with;
an RNA sequence (Figure 1: ORF)
a polypeptide-encoding nucleotide sequence in-frame with the initiation codon (Figure 1: His6); and
performing in vitro translation on the puromycin-RNA transcripts, wherein the puromycin covalently links the in-frame translated polypeptide to the puromycin-RNA transcript (Figure 1; p. 310, General Strategy: “Translation of these constructs in vitro results in the formation of a covalent bond between the RNA and the protein it encodes”); and
separating the polypeptide-RNA complexes from those without polypeptides (Figure 1: Nickel + anti-FLAG purification).
Cho does not disclose that the DNA fragments are cDNA fragments from a tumor. Cho does, however, teach that the method is useful for pre-screening to select for intact open reading frames, and the resultant library can be used for further functional screening.
Somers discloses a method for screening biologically-selected tumor-derived cDNA for identification of tumor-specific antigens using phage display (abstract). Based on the teachings of Cho, it would have been obvious to one of ordinary skill in the art to combine the method of Cho with the method of Somers, yielding the predictable result of pre-screening a biologically-selected tumor-derived cDNA library to select for intact open reading frames.
Cho also does not disclose that the polypeptide-encoding sequence contains out-of-frame stop codons in both the -1 and +1 frames. However, Cho does disclose that this method is intended to select for in-frame sequences, but it relies on the aberrant peptide not being enriched by affinity purification for the FLAG/His constructs as opposed to premature termination (p. 310, General Strategy: “Some [sequences] contain deletions and go out of frame and lack the N-terminal tag”).
Seligmann discloses a method by which out-of-frame translation is terminated by premature stop codons (abstract; p. 702, 1st ¶). Seligmann also teaches that the products of frameshift events can be deleterious, and their production tends to be a waste of energy and resources (p. 701, Introduction, 2nd ¶). Therefore, it would have been obvious to one of ordinary skill in the art by the effective filing date to adapt the teachings of Seligmann to the method of Cho, based on the motivation to prevent frameshifted translation, resulting in the addition of out-of-frame stop codons to the construct of Cho. Additionally, there would be a reasonable expectation of success as alteration of nucleotide sequences while preserving the encoded in-frame peptide sequence is commonly used for codon optimization and the like.
The differences between claim 1 and claim 2 are that, in claim 2, a polypeptide-encoding sequence is 5’ relative to the cDNA derived sequence, and there is an additional adapter sequence 3’ to the cDNA-derived sequence that contains the out-of-frame stop codons. Cho further discloses a polypeptide-encoding sequence 5’ relative to the cDNA-derived sequence (Figure 1: FLAG) and a sequence 3’ to the cDNA-derived sequence. All other recited limitations of claim 2 are also rendered obvious the disclosures of Cho, Somers, and Seligmann, as discussed above.
Regarding claims 5-6, Cho further discloses that the separating is performed using a reagent that binds to the polypeptide (Figure 1: Nickel + anti-FLAG purification) and the method further comprises an RT-PCR amplification on the complexes (Figure 1: RT-PCR).
Regarding claim 7, Somers further discloses inserting the cDNA library into a cloning vector (p. 2773, Materials and Methods, Cloning of a HT-29 tumor cell line…).
Regarding claims 8 and 9, Cho further discloses generating the library of RNA transcripts prior to (a) of claim 1 by performing a transcription reaction on a library of RNA expression constructs (p. 316, Construction of the random library) that each comprises: a transcription promoter (“phage T7 RNA polymerase promoter”), a translation initiation site (“initiating methionine”), DNA fragment (“random region”), a polypeptide encoding sequence (“FLAG tag”; “His6 tag”), and an adapter region (“flexible linker”). The use of cDNA fragments and out-of-frame stop codons are obvious over Somers and Seligmann, per the analysis of claim 1.
Cho et al., Somers et al., Seligmann et al., and Liu et al.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al., Somers et al., and Seligmann et al. as applied to claim 1 above, and further evidenced by Liu et al. (Meth. in Enzym. (2000), 318: 268-293). Cho further discloses that, “the RNA was produced from the cassette with T7 polymerase… as previously described” in Liu (p. 316, Construction of the random library). Liu teaches that the puromycin-tagged RNA transcripts are linked via ligation (p. 278-9, Ligation of mRNA and 3’-Puromycin Oligonucleotides), mediated by splint polynucleotides (“DNA splint”) that comprise, from 3’ to 5’: a sequence complementary to the 3’ end of the polypeptide-encoding sequence and a linker target sequence (p. 278: “the splint should overlap both the 3’ end of the mRNA and the 5’ end of the puromycin oligonucleotide”). Liu further discloses that the linker target sequence is a poly-dT sequence, and the target sequence is a poly-dA sequence (p. 279: 5’-TTTTTTTTTTAGCGCAAGA).
Cho et al., Somers et al., Seligmann et al., and Cieslik et al.
Claims 11, 20-21, 27-28, 41, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al., Somers et al., and Seligmann et al. as applied to claims 1, 5, and 8 above, and further in view of Cieslik et al. (Genome Res. (2015), 25: 1372-1381).
Regarding claims 11 and 20, the limitations of claim 1 are rendered obvious by the disclosures of Cho, Somers, and Seligmann, as discussed above. They do not disclose enriching the cDNA fragments, however. Cieslik discloses a method of cDNA library preparation enriched for exome-containing cDNA fragments (Figure 1A: capture specific) and teaches that exome-capture improves library quality, particularly from clinical tumor samples (abstract; p. 1378, Discussion, 1st ¶). Therefore, it would have been obvious to one of ordinary skill in the art by the effective filing date to incorporate the cDNA library preparation method of Cieslik into the method of Cho, Somers, and Seligmann, based on the motivation to improve library quality. There would have been a reasonable expectation of success as Cieslik teaches that this method is robust to sample input and the goal of enriching coding RNAs would also be assisted by exome enrichment.
Regarding claim 21, Cieslik further discloses performing strand-specific random primed nucleic acid amplification on a population of cellular RNA fragments to generate a population of cDNA fragments (p. 1379, Library preparation and sequencing: stranded capture library; Supplemental Methods: steps 2, 4, and 13).
The disclosures of Cho, Somers, Seligmann, and Cieslik also render obvious all limitations of claims 21, 28, 41, and 57 as discussed in relation to claims 1, 5, 8, 11, and 20.
Regarding claim 27, Cieslik further discloses preparing the population of cellular RNA fragments from a sample (p. 1379, Cell culture: “RNA was isolated…”).
Cho et al., Somers et al., Seligmann et al., Liu et al., and Cieslik et al.
Claims 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al., Somers et al., Seligmann et al., Liu et al., and Cieslik as applied to claims 1, 3, 4, and 21 above.
Cho et al., Somers et al., Seligmann et al., Cieslik et al., and Iris et al.
Claims 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al., Somers et al., Seligmann et al., and Cieslik et al. as applied to claim 21 above, and further in view of Iris et al. (US Pat. No: 6221585).
Regarding claim 25, Iris discloses a method for enriching a population of cDNA fragments for mismatch-containing cDNA fragments by contacting the population of cDNA fragments with a MutS protein (col. 12, lines 32-63). Iris further discloses that this method can be used with cDNA derived from tissue samples, such as tumor samples (col. 28, lines 55-64). As such, the difference between the instant claim and the prior art is the lack of actual combination of the mismatch-enrichment method of Iris with the method of Cho, Somers, Seligmann, and Cieslik. Additionally, in combination both methods would perform the same function as they do separately, and the results of the combination would have been predictable as it would simply add another enrichment step to the cDNA library preparation. Therefore, it would have been obvious to one of ordinary skill in the art to combine the mismatch-enrichment method of Iris with the screening method of Cho, Somers, Seligmann, and Cieslik.
Claim 26 recites the same steps as claim 25, merely in the different order of exome-enrichment prior to mismatch-enrichment. With regard to the order of steps, the courts have ruled that the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946; In re Gibson 39 F.2d 975, 5 USPZ 230 (CCPA 1930; MPEP 2144.04 section IV C). In the instant case, the steps of exome-enrichment and mismatch-enrichment are taught by the prior art as discussed in relation to claim 25, and thus is prima facie obvious in the absence of new or unexpected results.
Double Patenting
Claims 1-2, 5-6, 8-9, and 21 of this application is patentably indistinct from claims 1-2, 5-6, 8-9, and 13 of Application No. 17927112. Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
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 1-2, 5-9, 11, 20-21, 24-28, 41, and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 8-11, 13, 17-18, 29-30, 50, and 54 of copending Application No. 17927112 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they disclose largely overlapping subject matter.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3-4 and 23-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of copending Application No. 17927112 in view of Liu et al. Liu discloses the use of splint polynucleotides to join RNA transcripts to puromycin-tagged linker polynucleotides. This renders the instant claims obvious in combination with claims 1 and 13 of the reference application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/ALEXANDRA OLSON/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
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