DETAILED ACTION
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 .
Preliminary Amendment
2. The preliminary amendment filed on April 3, 2023 has been entered.
Claims 15-23 are pending and examined on the merits herein.
Information Disclosure Statement
3. The Information Disclosure Statement (IDS) filed on November 10, 2022 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 for at least the following reasons. First, the IDS does not contain a space for the examiner’s initials as required by 37 CFR 1.98(a)(1)(ii). Second, the IDS does not include the application number of the instant application on each page as required by 37 CFR 1.98(a)(1)(i). Instead, the IDS consists of copies of the IDSs previously considered by the examiner in the parent application (US 15/754,194). As discussed in MPEP 609.02 II.A.2, the submission of such copies is “strongly discouraged” because of its potential to confuse the record.
Applicant is advised that all references considered in the parent ‘194 application have been considered in accordance with the guidance set forth in MPEP 609.02 II.A.2. Therefore, Applicant need not resubmit the IDS unless Applicant desires the cited references to be printed on any patent issuing from the instant application.
Applicant is also advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Applicant is further advised that a size fee statement (and fee if necessary) is required for any IDS filed on or after January 19, 2025. See, e.g., the Quick Reference Guide to the Information Disclosure Statement (IDS) Size Fee and Size Fee Assertion published on the USPTO website.
Drawings
4. The drawings filed on November 10, 2022 are objected to because not all of the text in Figures 2A, 4A, 7, 10, 11, 13, and 14 is legible. In particular, the highlighted portions of the nucleic acid sequences shown in these figures are blurry. One possibility would be to replace the highlighting with italics or perhaps a larger font.
Figure 12 is objected to because it appears to contain a typographical error where “R rimer” is recited twice for “R primer.”
Figures 2A, 2B, and 2D are objected to because not all of the oligonucleotide sequences contained in the figures are identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, the “Brief Description of the Drawings” section at page 6, para. 19 of the specification states that SEQ ID NO: 5 is the forward primer shown in Figure 2A and also the miR-16 RNA target in that figure, but SEQ ID NO: 5 is not identical to the miR-16 RNA sequence shown at the left-most portion of Figure 2A or the top-most sequence in Figure 2B. Para. 19 also uses SEQ ID NOs: 7 and 9 to refer to the other sequences in Figure 2B and SEQ ID NOs: 54-57 to identify the sequences in Figure 2D, but these sequences are not identical to the RNAs disclosed in the figures. It is further noted that it is unclear whether the Sequence Listing intends for SEQ ID NOs: 5, 7, 9, and 54-57 to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained each sequence are not labeled as a modified nucleotide as required by MPEP 2417.
Figure 3A, 3B, and 3D are objected to because not all of the oligonucleotide sequences contained in the figures are identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, the “Brief Description of the Drawings” section at page 6, para. 20 of the specification states that SEQ ID NO: 5 is the miR-16 RNA target in that figure, but SEQ ID NO: 5 is not identical to the miR-16 RNA sequence shown at the right-most portion of Figure 3A or the top-most sequence in Figure 3B. Para. 20 also uses SEQ ID NOs: 6 and 58 to refer to the other two sequences in Figure 3B and SEQ ID NOs: 59 and 60 to identify the sequences in Figure 3D, but these sequences are not identical to the RNAs disclosed in the figures. It is further noted that it is unclear whether the Sequence Listing intends for SEQ ID NOs: 6 and 58-60 to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
Figures 4A, 4C, and 4D are objected to because not all of the oligonucleotide sequences contained in the figures are identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, the “Brief Description of the Drawings” section in para. 21 of the specification states that SEQ ID NO: 5 is the miR-16 RNA target in Figure 4A and also the first sequence in Figure 4B, but SEQ ID NO: 5 is not identical to the miR-16 RNA sequence shown in the figures. As well, the sequence identifiers used to identify the other sequences in Figures 4C and 4D are not identical to the nucleic acids disclosed in the figures. As with Figures 2C, 2D, 3C, and 3D, it is unclear whether the Sequence Listing intends for the sequence identifiers used for Figures 4C and 4D to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
Figure 6B is objected to because the oligonucleotide sequences contained in the figures are not identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, the sequence identifiers used in para. 23 of the specification are not identical to the sequences disclosed in the figure. And, as with Figures 2C, 2D, 3C, and 3D, it is unclear whether the Sequence Listing intends for the sequence identifiers used for Figure 6B to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
Figures 7, 11, and 13 are objected to because not all of the oligonucleotide sequences contained in the figures are not identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, SEQ ID NO: 5 is used in paras. 24, 28, and 30 to identify the microRNA target, but SEQ ID NO: 5 does not match the sequence shown in the figures. And, as discussed above, it is not clear that SEQ ID NO: 5 is intended to be a DNA or RNA sequence because the sequence is labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
Figure 10 is objected to because not all of the oligonucleotide sequences contained in the figures are not identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, SEQ ID NOs: 64, 65, 56, and 57 are used in para. 27 to identify the microRNA targets, but these sequences do not match the sequences shown in the figure. And, as with Figures 2C, 2D, 3C, and 3D, it is unclear whether the Sequence Listing intends for these sequence identifiers used for Figure 10 to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
Figure 12 is objected to because not all of the oligonucleotide sequences contained in the figures are not identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, SEQ ID NOs: 59 and 60 are used in para. 29 to identify the microRNA targets, but these sequences do not match the sequences shown in the figure. And, as with Figures 2C, 2D, 3C, and 3D, it is unclear whether the Sequence Listing intends for these sequence identifiers used for Figure 12 to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
Figure 14 is objected to because not all of the oligonucleotide sequences contained in the figures are not identified with the appropriate sequence identifier. See MPEP 2422.02. More specifically, SEQ ID NOs: 67, 56, and 57 are used in para. 31 to identify the microRNA targets, but these sequences do not match the sequences shown in the figure. And, as with Figures 2C, 2D, 3C, and 3D, it is unclear whether the Sequence Listing intends for these sequence identifiers used for Figure 14 to be DNA or RNA sequences because the sequences are labeled “RNA,” but the thymines contained therein are not labeled as a modified nucleotide as required by MPEP 2417.
One way for Applicant to address the issue in, e.g., Figures 2A, 3A, and 4A would be to ONLY provide sequence identifiers for the miR-16 target sequence and the adapter in the “Brief Description of the Drawings” section of the specification. If Applicant wishes to further describe the positions of the primers and probes used in the method, Applicant could do so descriptively without using sequence identifiers. Applicant is cautioned against introducing any new matter via amendments to the specification.
Specification
5. The specification is objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 2A, 2B, and 2D. In particular, para. 19 of the specification states that SEQ ID NO: 5 is shown in Figure 2A and is the first sequence in Figure 2B, but this is not correct because SEQ ID NO: 5 is not identical to either of these sequences. Similarly, para. 19 uses SEQ ID NOs: 7 and 9 to identify the other two sequences in Figure 2B and SEQ ID NOs: 54-57 to identify the sequences in Figure 2D, but these sequences are not identical to the RNA sequences shown in the figures. As well, para. 19 states that SEQ ID NO: 21 is shown in Figure 2A, but SEQ ID NO: 21 is a DNA sequence rather than the hybrid RNA-DNA sequence shown in Figure 2A.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 3A, 3B, and 3D. In particular, para. 20 of the specification states that SEQ ID NO: 5 is shown in Figure 3A and is the first sequence in Figure 3B, but this is not correct because SEQ ID NO: 5 is not identical to either of these sequences. Similarly, para. 20 uses SEQ ID NOs: 6 and 58 to identify the other two sequences in Figure 3B and SEQ ID NOs: 59 and 60 to identify the sequences in Figure 3D, but these sequences are not identical to the RNA sequences shown in the figures. As well, para. 20 states that SEQ ID NOs: 34 and 34 are shown in Figure 3A, but these sequences do not appear in this figure.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 4A, 4C, and 4D. In particular, para. 21 of the specification states that SEQ ID NO: 5 is shown in Figure 4A, but this is not correct because SEQ ID NO: 5 is not identical to either of these sequences. Similarly, para. 21 states that SEQ ID NOs: 13, 43, and 44 are shown in Figure 4A, but these sequences do not appear in this figure. As well, the sequence identifiers used to identify sequences disclosed in Figures 4C and 4D do not match the sequences disclosed in the figures.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 6B. In particular, the sequence identifiers used in para. 23 to identify sequences disclosed in Figure 6B do not match the sequences disclosed in the figures.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figures 7, 11, and 13. In particular, paras. 24, 28, and 30 of the specification state that SEQ ID NO: 5 is shown in Figures 7, 11, and 13, but this is not correct because SEQ ID NO: 5 is not identical to the microRNA template shown in the figures.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 10. In particular, para. 27 of the specification states that SEQ ID NOs: 64, 65, 56, and 57 are shown in Figure 10, but this is not correct because these sequences are not identical to the microRNA templates shown in the figure.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 12. In particular, para. 29 of the specification states that SEQ ID NOs: 59 and 60 are shown in Figure 12, but this is not correct because these sequences are not identical to the microRNA templates shown in the figure.
The specification is also objected to because the “Brief Description of the Drawings” section contains errors with respect to the sequences disclosed in Figure 14. In particular, para. 31 of the specification states that SEQ ID NOs: 67, 56, and 57 are shown in Figure 14, but this is not correct because these sequences are not identical to the microRNA templates shown in the figure.
Nucleotide and/or Amino Acid Sequence Disclosures
6. Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
(1) Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. More specifically, the miR-16 target sequence in Figures 2A and 2B is not identified with the appropriate sequence identifier. Paragraphs 19 and 20 of the specification use SEQ ID NO: 5 to refer to this sequence, but SEQ ID NO: 5 is not identical to the RNA sequence shown in Figures 2A and 2B.
The other two sequences in Figure 2B and also the sequences in Figure 2D are also not identified with the appropriate sequence identifiers for the reasons set forth above in the “Specification” and “Drawings” sections.
Not all of the sequences in Figures 3A, 3B, 3D, 4A, 4C, 4D, 6B, 7, and 10-14 are identified with the appropriate sequence identifiers for the reasons set forth above in the “Specification” and “Drawings” sections.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
It is also noted that this application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that none of the uracil-containing sequences in the figures are present in the Sequence Listing.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
7. Claim 15 is objected to because of the following informalities. Replacing “by RT-PCR assay” in line 1 of step (d) with either “by RT-PCR” or “using an RT-PCR assay” is suggested to improve the grammar of the claim.
Claim 15 is also objected to because the word “to” is missing in the phrase “complementary the boundary” in line 2 of step (d).
Claim 17 is objected to because “Db adapter” should be replaced with “Db-adapter” to maintain consistency with claim 15.
Claim Rejections - 35 USC § 112(a) (New Matter)
8. 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.
Claims 21-23 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.
Claim 21, which is a new claim submitted in a preliminary amendment filed after the filing date, depends from claim 15 and recites “wherein the target RNAs are quantified in human cancer cells.” Claims 22 and 23 each depend from claim 21 and further limit the type of human cancer cells.
Applicant’s response filed with the preliminary amendment does not point to any specific portion(s) of the original disclosure as providing support for the subject matter of claim 21.
As discussed below in the indefiniteness rejection set forth below, the “in human cancer cells” language in claim 21 causes uncertainty as to whether or not the claim encompasses in situ amplification and detection. If claims 21-23 do encompass in situ amplification and detection, these claims contain new matter because the original disclosure fails to provide support for such detection. Thus, claims 21-23 are rejected under 35 U.S.C. 112(a) for containing new matter.
Claim Rejections - 35 USC § 112(a) (Lack of Enablement)
9. 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 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). These factors include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative
skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Each of these factors is discussed below.
Nature of the Invention
Claim 16 depends from claim 15 and requires the forward primer used in the RT-PCR method to be “complementary to a 5’ sequence of the target RNAs.” The claimed invention is classified in the unpredictable arts of molecular biology and biochemistry.
Relative Skill of the Ordinary Artisan
The ordinary artisan typically holds a graduate degree and has at least several years of post-graduate laboratory and/or clinical experience.
Breadth of the Claims
Claim 16 is not broad in scope.
State of the Prior Art
The prior art does not teach or suggest the claimed method because it fails to teach or suggest that a forward primer can function as a forward primer in an RT-PCR method when it is complementary rather than identical or substantially identical to a 5’ sequence in the target nucleic acid. See, for example, Singh et al. (International Journal of Advanced Research in Biological Sciences 2014; 1(7): 65-68) at page 68, column 2 – page 69, column 1 and also in Figure 9A, where the forward primer is identical to a portion of the 5’ sequence of the target nucleic acid. See also Figure 3 in Chen et al. (US 2013/0011840 A1) and the accompanying description in para. 46, where the forward primer (element 12) is substantially identical to the 5’ portion of the microRNA target (element 11).
Guidance Presented in the Application & Working Examples
The specification states that the forward primer may be complementary to a 5’ sequence of the target RNAs (see, e.g., page 5, para. 17). The specification does not contain anything to demonstrate that such a forward primer was successfully used in RT-PCR, though. Instead, the working examples only describe the conventional use of a forward primer (i.e., a forward primer that is identical to the 5’ sequence of the target RNA). In particular, see Supplementary Tables S1-S3, which describe the primers and adapters used in the working examples. For example, in Supplementary Table S1, the forward primer (SEQ ID NO: 20) is identical to a 5’ portion of the target miR-16 RNA (see Figure 2B for the miR-16 sequence), with the caveat that uracil in the target RNA is replaced with thymine in the forward primer.
Quantity of Experimentation & Unpredictability
In view of the limitations in the specification and prior art, the ordinary artisan would have to conduct a very large quantity of highly unpredictable experimentation to enable practice of the claimed methods. In particular, the ordinary artisan would have to determine that a PCR primer that is complementary rather than identical to a 5’ sequence in the target RNA could function in the required manner (i.e., as a forward PCR primer). This undertaking would be inventive and unpredictable since there is nothing in the disclosure or the prior art to indicate that this would be possible. Instead, based on the prior art and the specification, such a primer would apparently be oriented in the wrong direction and would not generate the desired PCR product. In other words, the required experimentation would be inventive in nature, would have to be conducted with essentially no guidance from the specification and prior art, and would have no guarantee of success.
In view of the foregoing, the method of claim 16 is not enabled.
Claim Rejections - 35 USC § 112
10. 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 15-23 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 15
Claim 15 is indefinite because its scope is not entirely clear. The claim appears to be missing a word, such as “providing,” at the beginning of step (a), and as a result, it is not clear whether the primers and adapters recited in step (a) must be provided as a single composition or if they may be provided separately. Applicant could address the issue by amending step (a) to recite “providing the following adapters and primers….” This would clearly indicate that the primers and adapters may be provided as a single composition or separately.
Claim 15 is also indefinite because it is unclear whether a single 3’-Db-adapter and probe combination must target multiple different target RNAs or if each different 3’-Db-adapter and probe combination targets a different target RNA. If the latter interpretation is correct, Applicant could address the issue by amending the claim to replace “target RNAs” in steps (a)(i) and (a)(vi) with “a target RNA” and “the target RNA,” respectively. Alternatively, Applicant could also amend the claim to more clearly indicate that different target RNAs are targeted by different 3’-Db-adapters and probes.
Claim 15 is further indefinite because the adapters and primers in step (a) are numbered (i), (iii), (iv), (v), and (vi). It is not entirely clear whether the omission of “(ii)” is a typographical error or if a required component of the assay was omitted.
Claim 16
Claim 16 is indefinite by way of its dependency on claim 15 and also because, analogous to claim 15, it is unclear whether a single forward primer must be capable of hybridizing to multiple different RNAs or if each different forward primer hybridizes to a different target RNA. Applicant could address the issue in the same ways suggested above for claim 15.
Claims 17-19
Claims 17-19 are indefinite since they depend from claim 15 and do not correct its indefiniteness issues.
Claim 20
Claim 20 is indefinite by way of its dependency on claim 15 and also because there is insufficient antecedent basis for “the target RNA.” Since claim 15 only recites “target RNAs,” it is not clear whether claim 20 intends to require one of multiple target RNAs to be miR-16 or if all target RNAs must be wild-type or variant forms of miR-16.
Claims 21-23
Claims 21-23 are indefinite by way of their dependency on claim 15 and also because the scope of claim 21, from which claims 22 and 23 depend, is not clear. Claim 21 states that “the target RNAs are quantified in human cancer cells.” The “in human cancer cells” language in the claim suggests an in situ method, but based on the specification, this does not appear to be Applicant’s intention. Instead, it appears that Applicant intends to require analysis of target RNAs isolated from human cancer cells (see, e.g., page 21, para. 83 of the specification). Since there is ambiguity as to the intended scope, though, these claims are indefinite.
Claim Rejections - 35 USC § 103
11. 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.
12. 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.
13. Claims 15 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (WO 2014/071322 A1) in view of Chen et al. (US 2013/0011840 A1), Kuersten (US 2010/0279305 A1), and Nichols et al. (Current Protocols in Molecular Biology 2008; Chapter 3: Unit 3.15, pp. 3.15.1-3.15.4).
The instant claims are drawn to a method for quantifying small RNAs. The method comprises using Rnl2 ligation to ligate an adapter (3’-Db-adapter) with a stem-loop structure to the 3’ end of a target RNA and amplifying and quantifying the resulting ligation products by RT-PCR. The RT-PCR uses a probe labeled with a 5’ fluorophore and a 3’ quencher and a DNA polymerase with 5’ exonuclease activity. As well, the probe targets the boundary between the target RNA and the 3’-Db-adapter. The claims are written using open, “comprising” language and do not exclude the use of additional reagents (e.g., 5’ adapters) or steps.
Regarding claim 15, Wong discloses methods for quantifying target small RNAs (abstract). The methods of Wong comprise ligating an adapter to each end of the target small RNA and using a method such as TaqMan® RT-PCR, which uses a DNA polymerase with 5’ exonuclease activity and a labeled probe, to amplify and quantify the ligation product (see, e.g., Fig. 1 and paras. 6, 8, 122, and 143-144). Wong further teaches that each of the two adapters used in the ligation step may have a stem-loop structure such that the resulting ligation product has a dumbbell-like structure (see, e.g., Fig. 4 and the description in paras. 18, 64, and 90). As well, as can be seen in Fig. 4, the 5’ and 3’ adapters of Wong respectively contain a 5’ and 3’ protruding sequence that hybridizes to the target small RNA. Wong additionally teaches that a TaqMan® RT-PCR assay may use a reverse transcription (RT) primer, a forward primer, a reverse primer, and a TaqMan® probe comprising a 5’ fluorophore and a 3’ quencher (see, e.g., Figure 1 and para. 143).
The method of Wong differs from the instant claim 15 in two ways, both of which are obvious.
First, Wong fails to teach that the TaqMan® probe, which corresponds to the claimed dual-labeled probe, targets the boundary of the target RNA and the 3’-Db-adapter. Designing the TaqMan® probe used by Wong this manner would have been prima facie obvious, though, in view of the teachings of Chen and MPEP 2144.07. Specifically, MPEP 2144.07 states that it is prima facie obvious to select a known material or method in the absence of unexpected results. In this case, no evidence of unexpected results with respect to the claimed manner of probe design has been presented, and the teachings of Chen indicate that a TaqMan® probe designed in the claimed way would be suitable for quantification in the method of Wong by describing quantification of a target small RNA using a TaqMan® probe designed to hybridize to the boundary between the target small RNA and an adapter ligated to the target small RNA (see, e.g., Figures 2B-2C and para. 45 of Chen). Chen also teaches in para. 45 that the design of such a TaqMan® probe is routine for the ordinary artisan. This is sufficient to establish a prima facie case of obviousness.
Second, Wong fails to teach that the ligation step in the disclosed method is an Rnl2 ligation, but this would have been obvious in view of the teachings of Kuersten, Nichols, and section 2144.07 of the MPEP. MPEP 2144.07 states that, in the absence of unexpected results, it is prima facie obvious to select a known material or method based on its suitability for the intended purpose. In this case, no evidence of unexpected results has been presented with respect to the claimed ligation step, and the teachings of Kuersten in Figure 3 and paras. 16, 76, 80, and 123-125 indicate that an Rnl2 ligation process is suitable for use in the method of Wong. This, in combination with the guidance provided in paras. 123-125 of Kuersten as well as Nichols at pages 3.15.3-3.15-4 concerning ligation reaction conditions and reagents, would have provided the ordinary artisan with a reasonable expectation of success in using an Rnl2 ligation step in the method of Wong. The foregoing is sufficient to establish a prima facie case of obviousness.
Thus, the method of claim 15 is prima facie obvious.
Further regarding claim 20, which depends from claim 15, the teachings of Wong indicate that the disclosed method is broadly applicable to a wide variety of small RNA targets, including microRNA (see, e.g., paras. 6, 52, and 83-84), but the reference fails to teach or suggest using miR-16 as the target RNA. Chen, though, provides motivation to select miR-16 as the target RNA by teaching that this microRNA is a desirable target for amplification and detection (see, e.g., Example 5 on page 13). The ordinary artisan would have had a reasonable expectation of success since the method of Chen is similar to Wong as both methods comprise adapter ligation followed by quantitative RT-PCR (see, e.g., Example 5 of Chen and also Figures 1-4). Thus, the method of claim 20 is also prima facie obvious.
Regarding claims 21-23, which depend directly or indirectly from claim 15, Wong teaches that microRNAs are a desirable detection target since they “have been implicated in a number of diseases including cancer, heart disease and neurological diseases, consequently, miRNAs are studied as diagnostic and prognostic biomarkers” (para. 3; see also para. 163). Wong further teaches that the disclosed methods may be used for diagnostic and/or prognostic purposes for diseases, including many types of cancer (paras. 25 and 167). The types of cancer contemplated by Wong include breast cancer and prostate cancer (paras. 25 and 167). Thus, Wong clearly suggests quantifying target RNAs associated with cancer. The reference also teaches use of a wide variety of sample types, including cells and tissue biopsies (para. 83), which suggests practicing the method suggested by the references using microRNA isolated from human cancer cells (e.g., human breast cancer cells or human prostate cancer cells). Thus, the methods of claims 21-23 are also prima facie obvious.
Thus, the methods of claims 15 and 20-23 are prima facie obvious in view of the combined teachings of the cited references.
14. Claims 15, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (US 2013/0011840 A1) in view of Wong et al. (WO 2014/071322 A1), Kuersten (US 2010/0279305 A1), and Nichols et al. (Current Protocols in Molecular Biology 2008; Chapter 3: Unit 3.15, pp. 3.15.1-3.15.4).
The instant claims are drawn to a method for quantifying small RNAs. The method comprises using Rnl2 ligation to ligate an adapter with a stem-loop structure to the 3’ end of a target RNA and amplifying and quantifying the resulting ligation products by RT-PCR. The RT-PCR uses a probe labeled with a 5’ fluorophore and a 3’ quencher and a DNA polymerase with 5’ exonuclease activity. As well, the probe targets the boundary between the target RNA and the adapter.
Regarding claim 15, Chen teaches a method for amplifying and quantifying target RNAs, including target microRNAs (see, e.g., the abstract, Figures 1-4, and paras. 8-13 and 45-47). The methods of Chen comprise hybridizing an adapter to the 3’ end of the target microRNA, extending the 3’ end of the adapter to reverse transcribe the target microRNA, and amplifying the resulting product by PCR using a forward and reverse primer in the presence of a detector probe to quantify the amount of the microRNA target (see, e.g., Fig. 4 and para. 47; see also Figs. 1-3 and paras. 44-46 for additional description).
Further regarding claim 15, the adapter of Chen contains a stem-loop portion as well as a 3’ sequence that hybridizes to the microRNA target (see, e.g., Fig. 1 and para. 44; see also Figs. 3-4 and paras. 46-47). The adapter may also be ligated to the 3’ end of the microRNA target (para. 51). Further, the probe may target the boundary of the target microRNA and the adapter (see, e.g., Fig. 2 and para. 45; see also Fig. 3 and para. 46). The probe may also contain a 5’ fluorophore and a 3’ quencher (see, e.g., Figs. 2-3 and paras. 45-46). As well, the amplification and quantification may be via RT-PCR using a DNA polymerase with 5’ exonuclease activity (see, e.g., Figs. 2-3 and paras. 45-46, where TaqMan® detection is discussed; see also paras. 39 and 43 for additional discussion of the TaqMan® assay).
Regarding claim 20, Chen teaches that the target RNA may be miR-16 (para. 46).
Regarding claim 21, Chen teaches that the method may be used to amplify and quantify microRNA targets present in A549 cells or HepG2 cells (para. 71). These cell lines are human cancer cell lines.
Chen does not teach all of the elements of independent claim 15. In particular, Chen fails to teach Rnl2 ligation as required by the claim. Chen also does not teach use of a separate RT primer as required by claim 15. Instead, Chen teaches performing reverse transcription by extending the 3’ end of the 3’ adapter (see, e.g., Figure 4 and para. 47).
Prior to the effective filing date of the claimed invention, though, it would have been prima facie obvious to use Rnl2 ligation to perform the adapter ligation step in the method of Chen. As discussed in MPEP 2144.07, it is prima facie obvious to select a known material or method based on its suitability for the intended purpose in the absence of unexpected results. In this case, no evidence of unexpected results has been presented with respect to the use of Rnl2 ligation, and the teachings of Kuersten in Figure 3 and paras. 16, 76, 80, and 123-125 indicated that an Rnl2 ligation process is suitable for use in the method of Chen. This, in combination with the guidance provided in paras. 123-125 of Kuersten as well as in Nichols at pages 3.15.3 – 3.15.4 concerning ligation reaction conditions and reagents, would have provided the ordinary artisan with a reasonable expectation of success in using an Rnl2 ligation step in the method of Chen.
It also would have been prima facie obvious to practice the method of Chen using a separate RT primer. Wong provides motivation to do so as well as a reasonable expectation of success by teaching that a universal RT primer can be used for reverse transcription in a similar method for amplifying and quantifying microRNA comprising adapter ligation and RT-PCR (see, e.g., the abstract, Figs. 1 and 4, and paras. 6, 8, 122, and 143-144).
Thus, the methods of claims 15, 20, and 21 are prima facie obvious.
15. Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (US 2013/0011840 A1) in view of Wong et al. (WO 2014/071322 A1), Kuersten (US 2010/0279305 A1), and Nichols et al. (Current Protocols in Molecular Biology 2008; Chapter 3: Unit 3.15, pp. 3.15.1-3.15.4) and further in view of Xia et al. (International Journal of Cancer 2008; 123: 372-379).
As discussed above, the teachings of Chen in view of Wong, Kuersten, and Nichols render obvious the methods of claims 15, 20, and 21.
As noted above, Chen teaches that the target RNA may be miR-16 (para. 46). The reference also discloses a forward primer for amplifying miR-16 in Figure 3 (element 12). See also the accompanying description in para. 46. As can be seen in Figure 3, the forward primer of Chen is quite similar to the instant SEQ ID NO: 5, containing the first 15 nucleotides of that sequence.
The primer of Chen differs from the instant SEQ ID NO: 5 by containing a 5’ tail that is five nucleotides in length. The primer of Chen also does not include the last 7 nucleotides of the instant SEQ ID NO: 5. The remainder of Chen does not disclose a forward primer that is SEQ ID NO: 5, and Wong, Kuersten, and Nichols do not remedy this deficiency.
Prior to the effective filing date of the claimed invention, though, it would have been prima facie obvious for the ordinary artisan to practice the method suggested by Chen in view of Wong, Kuersten, and Nichols using a forward primer that consists of SEQ ID NO: 5. As discussed in MPEP 2144.06 and 2144.07, respectively, it is prima facie obvious to substitute equivalents known to be useful for the same purpose or to select a known material or method based on its suitability for the intended purpose in the absence of unexpected results. In this case, no evidence of unexpected results has been presented concerning SEQ ID NO: 5, and the prior art of Xia teaches that SEQ ID NO: 5 is a suitable forward primer for amplifying miR-16 by RT-PCR in a method that also uses a stem-loop adapter/RT primer (see Table 1 and the “Quantitative RT-PCR for miRNA” section on page 373). Thus, the ordinary artisan would have considered the primer of Chen and the instant SEQ ID NO: 5 to be equivalents useful for the same purpose. The ordinary artisan also would have considered SEQ ID NO: 5 to be suitable for the intended purpose of amplifying miR-16. Thus, the method of claim 19 is prima facie obvious.
16. Claims 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (US 2013/0011840 A1) in view of Wong et al. (WO 2014/071322 A1), Kuersten (US 2010/0279305 A1), and Nichols et al. (Current Protocols in Molecular Biology 2008; Chapter 3: Unit 3.15, pp. 3.15.1-3.15.4) and further in view of Mattie et al. (Molecular Cancer 2006; 5: 24).
As discussed above, the teachings of Chen in view of Wong, Kuersten, and Nichols render obvious the methods of claims 15, 20, and 21.
Chen broadly teaches that the disclosed method may be applied to any microRNA target of interest (see, e.g., paras. 8, 25-26, and 75) and additionally discloses detecting microRNA isolated from human cancer cells in Example 15 (see para. 71, where the A549 and HepG2 cells are human cancer cell lines), but the reference fails to teach analyzing microRNA from human breast cancer cells or human prostate cancer cells as required by claims 22 and 23, respectively.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to apply the method suggested by Chen in view of Wong, Kuersten, and Nichols to microRNA targets of interest present in human breast cancer cells or human prostate cancer cells. Chen provides motivation to do so by teaching that the disclosed method is broadly applicable to any microRNA of interest (see, e.g., paras. 8, 25-26, and 75), and Mattie provides motivation to analyze microRNAs from human breast cancer and human prostate cancer cells by teaching that these cells contain microRNAs that may be useful as biomarkers (see, e.g., the abstract, page 2, page 5, and pages 10-11). The ordinary artisan would have had a reasonable expectation of success since the teachings of Chen cited above indicate that the disclosed method is broadly applicable to any microRNA target of interest. Mattie also provides a reasonable expectation of success by disclosing successful quantification of microRNA targets of interest from human prostate cancer cells via RT-PCR and TaqMan® detection (and pages 2, 4, and 11-12). Thus, the methods of claims 22 and 23 are prima facie obvious.
Double Patenting
17. 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-