DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
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 for the rejections set forth below 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.
Status of the Application
2. Applicant’s response filed on May 8, 2023 has been entered.
Claims 26, 27, 29, 30, and 32-49 are pending. Claims 26, 27, 29, 30, 32-36, and 43-49 are under examination. Claims 37-42 remain withdrawn from further consideration as being drawn to a nonelected invention.
It is also noted that many of the claims include changes that are not identified by the markings required by 37 CFR 1.121. For example, in claim 30, “a detectable entity” has been replaced with “a detectible entity” without markings to identify this change. As well, “15 or more nucleotides” in claim 29 is replaced with “10 or more nucleotides,” but the markings in the claim set do not identify this change.
The new matter rejection and comments in the “Priority” section have been modified in a way not necessitated by the claim amendments. The anticipation rejection citing Ito has also been modified in a way not necessitated by the claim amendments. This Office action is made NON-FINAL for at least these reasons.
Response to Arguments
3. Applicant’s arguments filed on April 12, 2023 and entered with the response of May 8, 2023 have been fully considered.
Priority
Applicant argues that the claims under examination do, in fact, find support in the prior-filed applications (Remarks, page 7). In particular, Applicant points to the following portions of published versions of the prior-filed Applications: (1) col. 7, ll. 39-47 in US 10,745,749 (issued from parent Application Serial No. 15/796,982); (2) col. 7, ll. 35-43 in US 9,834,817 (issued from parent Application Serial No. 13/841,842); and (3) para. 42 in WO 2012/151560 (published version of PCT/US2012/036678).
In response, these portions of the prior-filed applications have been reviewed, as have the amendments to independent claim 26. They do not provide support for the full scope of claim 26, though, which continues to encompasses compositions in which neither of the first and second binding sequences is complementary to a region that potentially contains a variant nucleotide. The cited portions of the prior-filed applications only provide support for a composition in which the forward primer and/or the second binding sequence is complementary to a region that potentially contains a nucleotide variant. Accordingly, when neither the forward primer nor the second binding sequence is complementary to a region potentially containing a variant nucleotide, the instant claims under examination (i.e., claims 26, 27, 29, 30, 32-36, and 43-49) have an effective filing date of July 13, 2020 (i.e., the filing date of the instant application).
Objections to the Drawings
Applicant argues that the objections to the drawings should be withdrawn for the following reasons (Remarks, pages 7-8): (1) the instant application is a continuation of US Application Serial No. 15/796,982, which is a continuation of US Application Serial No. 13/841,842, each of which issued as US patents and contained the same figures; (2) replacement Figures 1 and 2 do not include an “A” or a “B” label; and (3) “FIGs. 1 & 2 were obtained from the literature simply to illustrate how fluorescence energy transfer operates…and does not reflect the primer-switch technology of the present invention.”
Applicant’s arguments in (1) and (2) above were persuasive. Those bases for objection have been withdrawn. And, more specifically as to (1), although the scanned figures are blurry, the figures in the file containing the figures for download are not. The objection concerning figure legibility has been withdrawn accordingly.
Applicant’s argument in (3) was not persuasive, however. The examiner agrees that the portions of Figures 1 and 2 in question illustrate how FRET works and do not describe inventive aspects of the application. The problem, though, is that it is not clear whether the hashed lines immediately above the letter “Y” and “C” are simply lines/dashes or if they are blurred nucleotides. If the former is correct, no sequence identifiers are necessary. If the latter is correct, sequence identifiers are necessary per MPEP 2422.02. Clarification is to whether the hashed lines are dashes or nucleotides is requested.
The drawings remain objected to because not all of Applicant’s arguments were persuasive.
Objections to the Specification
Applicant argues that the issue concerning support for the subject matter of claim 30 is moot in view of the amendments to that claim (Remarks, page 8). Applicant also argues that the objection concerning the continuity information has been addressed by the amendment to the specification (Remarks, page 9).
These arguments were persuasive. Those bases for objection have been withdrawn.
Applicant also argues on page 8 of the Remarks that an acceptable Sequence Listing was filed in the parent application. Here, Applicant also argues that a PDF copy of the Sequence Listing, which is identical to the CRF, has been filed with the response.
In response, Applicant’s submission of a PDF copy of the Sequence Listing is acknowledged. The objection made previously has been withdrawn. It is noted that submission of a PDF was not necessary to address the objection. Amending the paragraph in the specification that incorporates by reference the Sequence Listing to give the file size in bytes rather than kilobytes would have been sufficient.
Objection to claim 31
Applicant argues that the objection is moot since claim 31 was canceled in the response (Remarks, page 8).
This argument was persuasive. The objection has been withdrawn.
Rejection of claims 26, 28-30, 32, 33, 35, and 36 under 35 U.S.C. 101
Applicant argues that the rejection should be withdrawn in view of the amendments to claim 26, which require the first and second binding sequences to be covalently linked (Remarks, page 9).
This argument was not persuasive because the amendments to claim 26 encompass, but do not require, require covalent linking of the first and second binding sequences. As discussed in the rejection, amended claim 26 still encompasses non-covalent linkage via hybridization. The rejection has been maintained with modifications.
Rejection of claims 26-36 under pre-AIA 35 U.S.C. 112, first paragraph (new matter)
Applicant argues that the rejection should be withdrawn (Remarks, pages 9-10). In particular, Applicant argues that the subject matter at issue in claim 26 finds support in the instant application and points to the portions of the parent applications cited in the arguments concerning the effective filing date (Remarks, page 9). These portions correspond to para. 82 in the specification of the instant application. Applicant also argues that the amendments to claims 30 and 32-34 have been amended such that they do not contain new matter (Remarks, page 10).
These arguments have been fully considered and are persuasive in part. Applicant’s arguments as to claim 26 were unpersuasive for the reasons set forth above in the subsection of the Response to Arguments that addresses the effective filing date (i.e., the “Priority” subsection). Applicant’s argument regarding claims 30, 32, and 34 was persuasive. Those bases for rejection have been withdrawn. Applicant’s argument regarding claim 33 was not persuasive, though, because the amended claim still contains new matter for the reasons set forth in the modified rejection. Since Applicant’s arguments were not persuasive with respect to all aspects of the rejection, claims 26, 27, 29, 30, 32-36, and 43-49 remain rejected under pre-AIA 35 U.S.C. 112, first paragraph for containing new matter.
Rejection of claim 34 under pre-AIA 35 U.S.C. 112, second paragraph
Applicant argues that the rejection should be withdrawn in view of the amendments to claims 30 and 34 (Remarks, page 10).
This argument was persuasive. The rejections have been withdrawn.
Rejection of claims 26-28 and 30-33 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Ito as evidenced by Abigail, Kilger, Ward, and De Both
Applicant argues that the rejection should be withdrawn (Remarks, pages 10-11). In particular, Applicant argues that the rejection should be withdrawn because the compositions disclosed in Ito do not include the forward primer required by independent claim 26 (Remarks, page 11).
This argument was not persuasive. The application does not define the term “primer,” but a reasonable interpretation is that the 3’-terminus of a primer is not attached to a solid support. Ito meets this requirement by teaching that the 5’ end or the 3’ end of the oligonucleotides shown in Figures 1 and 2 may be attached to the solid support. It is not clear whether the fluorescent labels attached to the ends of the oligonucleotides shown in Figure 1 and 2 of Ito are attached at the 3’ end or if they are attached near the 3’ end. If the labels are attached near the 3’ end, the oligonucleotides of Ito are primers since their 3’ ends are available for extension in a polymerase-mediated reaction. And, even if the labels in Ito are attached at the 3’ end of the oligonucleotides shown in Figures 1 and 2, said oligonucleotides may still be considered “primers” since multiple prior art references use the term “primer” to describe an oligonucleotide with a label at the 3’ end. See, e.g., Wang et al. (US 2003/0138830 A1) at para. 6; Belouchi et al. (US 2002/0155449 A1) at paras. 54 and 61; and Wittwer et al. (US 2002/0058258 A1) at paras. 369, 407, and 412.
Since Applicant’s argument was not persuasive, the rejection has been maintained with modifications.
Rejection of claims 26-28 and 30-36 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Satterfield
Applicant argues that the rejection should be withdrawn because Satterfield does not qualify as prior art (Remarks, pages 11-12).
This argument was not persuasive because Applicant’s arguments regarding the effective filing date of the claims under examination were unpersuasive for the reasons set forth above. More specifically, the cited portions of Satterfield do not disclose a composition in which the first and/or second binding sequence is complementary to a region that potentially contains a variant nucleotide. As discussed above, the original disclosure does not provide support for compositions in which the first and/or second binding sequence is not complementary to a region that potentially contains a variant nucleotide. Thus, Satterfield does qualify as prior art, and the rejection has been maintained with modifications to address the claim amendments.
Rejection of claim 29 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ito as evidenced by Abigail, Kilger, Ward, and De Both and in view of Mueckstein
Applicant argues that the rejection should be withdrawn because the secondary reference, Mueckstein, does not remedy the deficiencies in Ito with respect to claim 26, from which claim 29 depends (Remarks, page 12).
This argument was not persuasive because Ito is not deficient for the reasons set forth above and in the modified rejection. The rejection has been maintained.
Double Patenting rejections citing US 10,745,749
Applicant states that a terminal disclaimer will be filed when the instant claims are allowable (Remarks, pages 12-13).
Applicant’s remarks are acknowledged. The rejections have been maintained with modifications since they remain applicable.
Priority
4. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120, 365(c), and 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of all of the prior-filed applications, i.e., US Application Serial Nos. 13/841,142 and US Application Serial No. 15/796,982; Provisional Application Serial No. 61/482,576; and PCT/US2012/036678, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for the full scope of one or more claims of this application. As discussed in greater detail below in the new matter rejection, claims 26, 27, 29, 30, 32-36, and 43-49, none of which is an originally filed claim, encompass compositions in which neither the forward primer nor the second binding sequence is complementary to a region that potentially contains a variant nucleotide. The prior-filed applications, which contain, at most, the same disclosure as the original disclosure, fail to support the full scope of the instant claims under examination for the same reasons set forth in the new matter rejection below. Accordingly, when neither the forward primer nor the second binding sequence in the composition is complementary to a region that potentially contains a nucleotide variant, the instant claims 26, 27, 29, 30, 32-36, and 43-49 have an effective filing date of July 13, 2020 (i.e., the filing date of the instant application).
Drawings
5. The drawings filed on July 13, 2020 are objected to because of the following informalities: Each of Figures 1 and 2 appears to disclose three oligonucleotide sequences, but the “Brief Description of the Drawings” section only discloses one sequence (SEQ ID NO: 31). If the sequences are not the same, they must be described with the appropriate sequence identifier per MPEP 2422.02. As well, if the hashed lines above the letters “Y” and “C” in each of Figs. 1 and 2 are merely dashes and not blurry nucleotides, Applicant could address objection by stating as much in the next response.
Claim Objections
6. Claim 26 is objected to because line 5 recites --3’’-- for --3’--. The claim also contains several instances of “complimentary” for “complementary.”
Claim 27 is objected to because of the following informalities: Applicant may wish to replace “extendible” with “extendable” to maintain consistency with the spelling used in the specification.
Claim 29 is objected to because it recites “complimentary” for “complementary.” As well, replacing “or 10 or more nucleotides” with “more than 10 nucleotides” or “15 or more nucleotides” is suggested.
Claims 30, 32, and 34 are objected to because of the following informalities: Applicant may wish to replace “detectible” in each claim with “detectable” to maintain consistency with the spelling used in the specification.
Claims 47 and 48 are objected to because the recite “complete” for “compete.” As well, in the last line of claim 48, replacing “nucleic acids” with “nucleotides” is suggested because the latter appears to more accurately capture Applicant’s meaning.
Claim Rejections - 35 USC § 101
7. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 26, 29, 35, 36, and 43-49 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claim 26 is directed to a composition that comprises a first binding sequence linked or conjugated to a second binding sequence. The first binding sequence is a forward primer that is complementary to a sequence in a target region of a nucleic acid. The second binding sequence is complementary to either (i) a sequence that overlaps with the sequence to which the forward primer is complementary, or (ii) a sequence that is 5’ of the sequence to which the forward primer is complementary. The specification teaches that nucleic acids may be linked to one another via hybridization (page 18, para. [0080]).
Claim 26 encompasses naturally occurring products when the first and second binding sequence are non-covalently linked by hybridization to one another for the following reasons. First, since the claim does not require the first and second binding sequences to contain any non-naturally occurring nucleotides or other non-naturally occurring elements, each of these two sequences may simply be a short piece of DNA or RNA that is complementary to a naturally occurring region in a target nucleic acid. Then, when the forward primer (i.e., the first binding sequence) and the second binding sequence are non-covalently linked by hybridization, the resulting product is simply two naturally occurring products that are not linked by any non-naturally occurring material and do not perform any function other than their natural function of hybridization to a complementary sequence.
The judicial exception in claim 26 is not integrated into a practical application because the claim only recites the judicial exception and is not limited to any particular application(s).
Claim 26 also does not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not require any non-naturally occurring structural elements in addition to the naturally occurring features discussed above. Also, the forward primer and the second binding sequence perform the same functions in the claimed composition as they do in nature – hybridization to a complementary nucleic acid. Thus, claim 26 is directed to a judicial exception without significantly more.
Claim 29 depends from claim 26 and requires the second binding sequence to be complementary to a sequence that overlaps with the sequence to which the first binding sequence is complementary. This claim also encompasses a judicial exception without significantly more for the reasons set forth above with respect to claim 26.
Claim 35 depends from claim 26 and requires the first and second binding sequences to not be attached to a solid support. Claim 36 also depends from claim 26 and requires the composition to further include a reverse primer. These claims encompass naturally occurring nucleic acids and are directed to a judicial exception without significantly more for the reasons set forth above with respect to claim 26.
Claims 43-49 depend directly or indirectly from claim 26 and set forth further limitations concerning the sequence features of the forward primer and second binding sequence. These claims encompass naturally occurring nucleic acids for the reasons set forth above with respect to claim 26.
In view of the foregoing, claims 26, 29, 35, 36, and 43-49 are not directed to eligible subject matter and are rejected under 35 U.S.C. 101.
Amending the claims to require covalent linking of the first and second binding sequences would overcome the rejection as would amending the claims such that non-covalently linked sequences do not encompass two naturally occurring nucleic acids that are linked to one another via hybridization. Alternatively, Applicant could incorporate the subject matter of claim 32 to address the rejection.
Claim Rejections - 35 USC § 112
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 26, 27, 29, 30, 32-36, and 43-49 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 26
Claim 26 is drawn to a composition comprising a first binding sequence linked or conjugated to a second binding sequence. The first binding sequence is a forward primer and is complementary to a target region on a nucleic acid. The second binding sequence is complementary to either (i) a region that overlaps with the region to which the forward primer is complementary, or (ii) a region located 5’ of the region to which the forward primer is complementary.
Claim 26 contains new matter because it encompasses compositions in which neither of the first and second binding sequences is complementary to a region that potentially contains at least one nucleic acid variant. As discussed in para. 82 of the specification, for example, either the first binding sequence or the second binding sequence binds to a region potentially containing at least one variant, and as can be seen in Fig. 19, for example, this allows for better mutation detection. The original disclosure only describes compositions in which the first or second binding sequence is complementary to a region that may contain a variant. Accordingly, the broader scope in claim 26, where neither sequence is required to be complementary to a region potentially containing a variant, is not supported by the original disclosure, and the claim is rejected for containing new matter.
Claims 27, 29, 30, 32-36, and 43-49 also contain new matter since they depend from claim 36 and do not correct its new matter issue.
Claims 33 and 34
As discussed below in the indefiniteness rejection, it is unclear whether the fluorescent label and quencher recited in claim 33 correspond to the detectable entity in claim 30, from which claim 33 depends.1 As a result, claim 33 encompasses the following: (i) compositions in which the second binding sequence is attached to a fluorescent label and a quencher, (ii) compositions in which the second binding sequence is attached to a fluorescent label or a quencher, and (iii) compositions in which the fluorescent label and quencher are not attached to the second binding sequence (i.e., compositions in which one or both of the fluorescent label and quencher are attached to the forward primer as well as compositions in which the fluorescent label and quencher are not attached to the forward primer or the second binding sequence).
The original disclosure describes attaching the detectable entity, which may be a FRET pair, to the second binding sequence (para. 75, for example) or to either or both of the first and second binding sequences (original claims 9 and 10). This disclosure is insufficient to support the many other compositions encompassed by the claims (e.g., compositions in which the neither of the fluorescent label and quencher is attached to the forward primer or the second binding sequence). Thus, claim 33 (and claim 34, which depends from claim 33) contain new matter for an additional reason.
Claim Rejections - 35 USC § 112
9. 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 26, 27, 29, 30, 32-36, and 43-49 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 26 has been amended to recite “wherein said first binding sequence is a forward primer” in lines 3-4. The claim also recites “said forward primer of said first binding sequence” in line 10. This latter recitation is a broader statement of the recitation in lines 3-4 because it encompasses first binding sequences containing elements in addition to a forward primer sequence. As discussed in MPEP 2173.05(c), a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. In this case, claim 26 is indefinite because there is a question or doubt as to whether the feature introduced by the narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Applicant could address the issue by replacing “forward primer of the first binding sequence” with “forward primer.”
Claims 27, 29, 30, 32-36, and 43-49 are also indefinite since they depend from claim 26 and do not remedy its indefiniteness issue.
Claim 33 is further indefinite because the structural requirements of the composition are not entirely clear. Claim 33 depends from claim 30, which has been amended to require the detectable entity to be attached to the second binding sequence. Claim 33 recites, “The composition according to claim 30, comprising a fluorescent label and a quencher.” It is not clear whether this fluorescent label and quencher in claim 33 correspond to the detectable entity recited in claim 30 or if they are separate therefrom. Based on claim 34, which depends from claim 33, it appears that the former was intended. If this is correct, Applicant could amend claim 33 to recite “The composition of claim 30, wherein the detectable entity is a fluorescent label and a quencher.”
Claims 43 and 44 are further indefinite for the following reason. These claims require the second binding sequence to be fully complementary to the target region sequence in the absence of (claim 43) or the presence of (claim 44) said nucleic acid variant. This language in claims 43 and 44 suggests that the target region sequence potentially contains the nucleic acid variant, but it is not entirely clear from the claim language in claims 43 and 44 or claim 26, from which they depend, that this is the case. Applicant could address the issue by amending claim 26 to require the target region sequence to potentially contain said nucleic acid variant.
Claim 47 is indefinite because there is insufficient antecedent basis for “said target region sequence that does not contain said nucleic acid variant.” This limitation is recited in the last two lines of the claim.
Claim Rejections - 35 USC § 112
10. 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 45 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 45 depends from claim 26 and recites “wherein said forward primer is fully or partially complementary to said target region sequence.” This is not further limiting because it is already required by claim 26. More specifically, claim 26 requires the first binding sequence, which is a forward primer, to be complementary to a target region sequence of a nucleic acid. This language in claim 26 necessarily encompasses full or partial complementarity. Accordingly, claim 45 is not further limiting. Applicant could address the issue by presenting the two options--full complementarity and partial complementarity--in separate dependent claims.
Applicant may cancel the claim, amend the claim to be in proper dependent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
11. The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
12. Claims 26, 27, 30, 32, 33, and 45 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Ito et al. (JP 2006-166808 A) as evidenced by Abigail et al. (US 6,004,513), Kilger et al. (US 6,399,304 B1), Ward et al. (US 2003/0059786 A1), De Both et al. (US 2013/0330774 A1), Wang et al. (US 2003/0138830 A1), Belouchi et al. (US 2002/0155449 A1), and Wittwer et al. (US 2002/0058258 A1).2
The instant claims are drawn to a composition comprising a first binding sequence and a second binding sequence. The two binding sequences are linked or conjugated to one another. The first binding sequence is a forward primer that is complementary to a target region of a nucleic acid. The second binding sequence is complementary to either (i) a region that overlaps with the region to which the forward primer is complementary, or (ii) a region 5’ of the region to which the forward primer is complementary.
Ito discloses a composition that meets all of the requirements of claim 26 in Figures 1 and 2, which are reproduced below.
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In Figure 1, any two of probe elements 12-15 correspond to the first and second binding sequences of the claimed composition (see also paras. 148-149 and 28-30, 32, 33, 37-38, and 51-53 for additional description). In Figure 2, any of probe elements 22-24 correspond to the second binding sequence, and probe element 25 corresponds to the claimed forward primer (see also paras. 148-149 as well as paras. 28-29, 31-33, 37-38, and 51-53 for additional description). The different probe elements may be covalently linked (e.g., to linker 11 in Figure 1 or to one another, optionally via linkers, as shown in Figure 2) (see also paras. 37-38, 53, and 56-58, for example), and this linkage need not occur at the 3’ end of the forward primer (see paras. 53 and 56-58, where Ito teaches that the linker may be attached to the 5’ or 3’ end of each probe element). In other words, when the 5’ end of any of probe elements 12-15 in Figure 1 is attached to linker 11 or when probe element 25 is attached to probe element 24 via its 5’ end, said probes correspond to the claimed forward primer.
Ito further teaches that one probe element may detect a wild-type nucleic acid and another probe element(s) may detect a variant nucleic acid, with the different probe elements hybridizing to the same region of the nucleic acid and differing at the polymorphic site (paras. 34, 36, 51, and 67-68), thus meeting the requirement in claim 26 for each of the binding sites to hybridize to a region on the same strand of a target nucleic acid.
As well, it is noted that the instant application does not define the term “primer,” but a reasonable interpretation is that the 3’-terminus of a primer is not attached to a solid support, since an oligonucleotide attached at the 3’ end to a solid support would be unable to undergo polymerase-mediated extension. Ito satisfies this interpretation by teaching that the 5’ end or the 3’ end of the oligonucleotides shown in Figures 1 and 2 may be attached to the solid support. It is not clear whether the fluorescent labels attached to the ends of the oligonucleotides shown in Figure 1 and 2 of Ito are attached at the 3’ end or if they are attached near the 3’ end. If the labels are attached near the 3’ end, the oligonucleotides of Ito are primers since their 3’ ends are available for extension in a polymerase-mediated reaction. As well, even if the labels in Ito are attached at the 3’ end of the oligonucleotides shown in Figures 1 and 2, said oligonucleotides may still be considered “primers” since multiple prior art references use the term “primer” to describe an oligonucleotide with a label at the 3’ end. See, e.g., Wang et al. (US 2003/0138830 A1) at para. 6; Belouchi et al. (US 2002/0155449 A1) at paras. 54 and 61; and Wittwer et al. (US 2002/0058258 A1) at paras. 369, 407, and 412.
Lastly, the disclosure of Ito also meets the requirement in claim 26 for the second binding sequence to be complementary to a sequence that overlaps with the sequence to which the forward primer is complementary because, as evidenced by each of De Both, Kilger, Ward, and Abigail, “overlapping sequences” are not limited to partially overlapping sequences and also encompass sequences that completely overlap (see De Both at para. 81; Ward at paras. 20 and 33; Kilger at column 14, lines 28-39; and Abigail at column 7, lines 53-60). Therefore, although Ito does not disclose the nucleotide sequences of the different probe elements shown in Figures 1 and 2, by teaching that these probe elements hybridize to the same region of a target nucleic acid and differ at a polymorphic site in the nucleic acid, the reference also teaches that the probe element(s) that correspond to the claimed selector blocker have a sequence that overlaps with the sequence to which probe element corresponding to the forward primer is complementary.
Thus, Ito anticipates the composition of claim 26.
Regarding claim 27, Ito teaches a composition in which the second binding sequence is not extendible. Specifically, in Figure 2, the regions that correspond to the second binding sequence (i.e., elements 22-24) are not extendible.
Regarding claims 30, 32, and 33, Ito teaches that the disclosed composition may include fluorescent labels that are useful in FRET methods (i.e., fluorophores and quenchers) (machine translation, paras. 30-32 as well as paras. 40-43). As can be seen in Figures 1 and 2, the labels may be attached to the second binding sequence.
Regarding claim 45, as noted above in the discussion of the teachings of Ito with respect to claim 26, any two of probe elements 12-15 in Figure 1 correspond to the first and second binding sequences of the claimed composition. As well, in Figure 2, any of probe elements 22-24 correspond to the second binding sequence, and probe element 25 corresponds to the forward primer (i.e., first binding sequence in the claimed composition). Ito further teaches that one probe element may detect a wild-type nucleic acid and another probe element(s) may detect a variant nucleic acid, with the different probe elements hybridizing to the same region of the nucleic acid and differing at the polymorphic site (paras. 34, 36, 51, and 67-68). Therefore, Ito meets the requirement in claim 45 for the forward primer (i.e., the first binding sequence) to be partially or fully complementary to the target region sequence.
13. Claims 26, 27, 30, 32-36, and 45 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Satterfield (US 2014/0038182 A1).3
The instant claims are drawn to a composition comprising a first binding sequence and a second binding sequence. The two binding sequences are linked or conjugated to one another. The first binding sequence is a forward primer that is complementary to a target region of a nucleic acid. The second binding sequence is complementary to either (i) a region that overlaps with the region to which the forward primer is complementary, or (ii) a region 5’ of the region to which the forward primer is complementary.
Regarding claim 26, Satterfield discloses a composition containing an oligonucleotide that contains a first and second binding sequence as set forth in the instant claim (see, e.g., Figs. 3 and 5 and paras. 13 and 15; see also paras. 9, 25, and 52 and Example 1 on page 16). In particular, the oligonucleotides discussed in these portions of Satterfield contain an extendible primer sequence that is complementary to a target region sequence of a target nucleic acid. This primer sequence corresponds to the “first binding sequence” recited in the claims. The oligonucleotides of Satterfield also contain a capture portion that is linked to the 5’ end of the primer portion via a linker and hybridizes to a region 5’ of the region to which the 3’ primer sequence hybridizes (see, in particular, Figs. 3 and 5). This 5’ capture portion corresponds to the “second binding sequence” recited in the claim. Satterfield additionally teaches that the primer sequence may be a forward primer sequence in Example 1 on page 16. And, further regarding the amendment to the preamble, the composition in Satterfield is capable of being used to detect the presence or absence of a nucleic acid variant. For example, the composition may be used in a primer extension method designed to determine the identity of the nucleotide at a variable position located immediately downstream of the primer. Thus, Satterfield teaches all of the elements of the instant claim 26.
Regarding claim 27, Satterfield teaches that the second binding sequence (i.e., the capture probe portion of the disclosed oligonucleotides) is not extendible. See, e.g., Fig. 5 and also Example 1 on page 16, where the 3’ end of the capture portion is blocked with a quencher (DABCYL).
Regarding claims 30, 32, and 33, Satterfield teaches that the second binding sequence (i.e., the capture probe portion) may contain a detectable entity (see, e.g., Fig. 5 and Example 1 on page 16). In Example 1, the reference discloses the use of a FRET pair that includes a fluorophore and a quencher.
Regarding claim 34, Satterfield also teaches that method may include unquenching of the detectable entity during extension of the forward primer (see, e.g., Fig. 5 and also para. 15).
Regarding claim 35, the oligonucleotides of Satterfield are not provided on a solid support. See, e.g., Example 1 on page 16.
Regarding claim 36, the composition of Satterfield may additionally include a reverse primer (Example 1 on page 16).
Regarding claim 45, as noted above, the claim is not further limiting. Also, as discussed above, Satterfield discloses a forward primer sequence that binds to the target region of the target nucleic acid. Such a sequence is necessarily fully or partially complementary to the target region sequence.
Claim Rejections - 35 USC § 103
14. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
15. Claim 29 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ito et al. (JP 2006-166808 A) as evidenced by Abigail et al. (US 6,004,513), Kilger et al. (US 6,399,304 B1), Ward et al. (US 2003/0059786 A1), De Both et al. (US 2013/0330774 A1) Wang et al. (US 2003/0138830 A1), Belouchi et al. (US 2002/0155449 A1), and Wittwer et al. (US 2002/0058258 A1) and in view of in view of Mueckstein et al. (BMC Bioinformatics 2010; 11: 35).4
Claim 29 depends from claim 26 and requires the forward primer and second binding sequence to target sequences that overlap by 1, 2, 3, 4, 5, 10 or 10 or more nucleotides.
As discussed above, Ito as evidenced by De Both, Kilger, Ward, Abigail, Wang, Wittwer, and Belouchi anticipates the compositions of claims 26, 27, 30, 32, 33, and 45.
Regarding claim 29, the probe elements of Ito, which correspond to the claimed forward primer and second binding sequence, may target the same target region but contain a different nucleotide at a potential polymorphic site (see, for example, paras. 34, 36, 51, 67-68, and 110-112 of the machine translation of Ito). Since Ito does not disclose the specific nucleotide sequences of these probe elements, it cannot be determined whether the overlapping region has a length within one of the ranges recited in claim 29.
The teachings of Ito in view of Mueckstein, though, render obvious the overlap lengths recited in claim 29. In particular, since the teachings of Mueckstein indicate that probes of several different lengths were known to be useful for conducting solid-phase hybridization assays (see, e.g., Table 1 on page 6, where the reference teaches that other authors have used probes of 25 or 45-75 nucleotides to conduct solid-phase hybridization assays), the ordinary artisan would have recognized that the probe elements in the oligonucleotides of Ito could have these lengths or similar lengths, and, accordingly, would have had both motivation and a reasonable expectation of success in so designing the oligonucleotides of Ito. The resulting probe elements, which would target the same region and contain different nucleotides at the polymorphic site, would also have an overlapping region of more than 15 nucleotides as encompassed by the range of “10 or more nucleotides” recited in claim 29. Thus, the composition of claim 29 is prima facie obvious.
16. Claims 43, 44, and 46-49 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ito et al. (JP 2006-166808 A) as evidenced by Abigail et al. (US 6,004,513), Kilger et al. (US 6,399,304 B1), Ward et al. (US 2003/0059786 A1), De Both et al. (US 2013/0330774 A1), Wang et al. (US 2003/0138830 A1), Belouchi et al. (US 2002/0155449 A1), and Wittwer et al. (US 2002/0058258 A1).5
As discussed above, the teachings of Ito as evidenced by Abigail, Kilger, Ward, De Both, Wang, Belouchi, and Wittwer anticipate the compositions of claims 26, 27, 30, 32, 33, and 45.
Regarding claims 43, 44, and 46-49, as noted above in the discussion of the teachings of Ito with respect to claim 26, any two of probe elements 12-15 in Figure 1 correspond to the first and second binding sequences of the claimed composition. As well, in Figure 2, any of probe elements 22-24 correspond to the second binding sequence, and probe element 25 corresponds to the forward primer (i.e., first binding sequence in the claimed composition). Ito further teaches that one probe element may detect a wild-type nucleic acid and another probe element(s) may detect a variant nucleic acid, with the different probe elements hybridizing to the same region of the nucleic acid and differing at the polymorphic site (paras. 34, 36, 51, and 67-68).
Ito does not teach all of the elements of claims 43, 44, and 46-49 for the following reasons. First, as to claims 43, 44, and 49, Ito does not specify whether the second binding sequence is fully or only partially complementary to the target region sequence in the absence (or presence) of the nucleic acid variant. As to claim 46, Ito does not state that the forward primer and second binding sequence compete for hybridizing (fully or partially) to the target region sequence. Then, since claims 47 and 48 depend from claim 46, Ito also does not meet their requirements.
The teachings of Ito render obvious the requirements set forth in claims 43, 44, and 46-49, however, for the following reasons.
As to claims 43, 44, and 49, it would have been prima facie obvious for the ordinary artisan to design the composition of Ito such that the second binding sequence is fully or partially complementary to the target region sequence in the presence (or absence) of the nucleic acid variant. The ordinary artisan would have recognized that either option (i.e., full or partial complementarity) would be suitable for using the composition of Ito, and, accordingly, would have been motivated to select either option with a reasonable expectation of success. Thus, the compositions of claims 43, 44, and 49 are prima facie obvious.
As to claims 46-48, it also would have been prima facie obvious for the ordinary artisan to design the composition of Ito such that the second binding sequence and forward primer compete for hybridizing (fully or partially) to the target region sequence. The ordinary artisan would have been motivated to design the forward primer sequence and the second binding sequence(s) in the compositions of Ito to have the same or similar lengths, recognizing that doing so would allow hybridization with the target region sequence to be conducted under one set of hybridization conditions. When such compositions are contacted with the target region sequence, the forward primer sequence and the second binding sequences will necessarily compete for hybridization (full or partial) with the target region sequence. As well, further regarding claim 48, since as noted above, Ito teaches that the compositions are designed to contain a portion complementary to the wild-type nucleic acid and at least one variant nucleic acid, such compositions will necessarily contain a forward primer sequence and a second binding sequence that differ from one another by at least one nucleotide (i.e., the nucleotide at the polymorphic position). Thus, the compositions of claims 46-48 are also 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
18. Claims 26, 27, 29, 30, 32-36, and 43-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 16 of U.S. Patent No. 10,745,749 B2.6
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘749 patent overlap in scope with the instant claims and teach or suggest all of their limitations. The instant claims are drawn to a composition comprising a first binding sequence and a second binding sequence. The two binding sequences are linked or conjugated. The first binding sequence is a forward primer that is complementary to a target region of a nucleic acid. The second binding sequence is complementary to either (i) a region that overlaps with the region to which the forward primer is complementary, or (ii) a region 5’ of the region to which the forward primer is complementary. See the instant claim 26.
Claim 1 of the ‘749 patent is drawn to an oligonucleotide that contains all of the features set forth in the instant claim 26, with the “selector blocker” in claim 1 of the ‘749 patent corresponding to the claimed “second binding sequence.” The oligonucleotide recited in claim 1 of the ‘749 patent is also suitable for detecting the presence or absence of a nucleic acid variant. See also claim 5. As well, claim 16 of the ‘749 patent is drawn to a kit comprising the oligonucleotide of claim 1. The oligonucleotide recited in claims 1 and 16 of the ‘749 patent also possesses additional requirements relative to the instant claim 26 because the second binding sequence is not extendable and functions as a steric blocker. Thus, claims 1 and 16 in the ‘749 patent recite a species of the composition claimed in the instant claim 26. As discussed in MPEP 804 II.B.1, a species claim in a conflicting patent or copending application anticipates a more generic claim. Therefore, the instant claim 26 is not patentably distinct from the claims of the ‘749 patent.
The limitations of the instant claim 27, which depends from the instant claim 26, are recited in claims 1 and 16 of the ‘749 patent.
The limitations of the instant claim 29, which depends from the instant claim 26, are recited in claim 4 of the ‘749 patent.
The instant claim 30, which depends from the instant claim 26, requires the composition to contain a detectable entity attached to the second binding sequence. The instant claim 32, which depends from the instant claim 30, requires the detectable entity to be a FRET pair, fluorescent label, or a chemiluminescent label, and the instant claim 33, which also depends from the instant claim 30, requires the composition to contain a fluorescent label and a quencher. Claim 9 of the ‘749 patent states that the primer-switch, which includes the forward primer and second binding sequence of the instant composition, comprises a detectable entity. Claim 10 of the ‘749 patent states that the detectable entity may be a fluorescent label, a chemiluminescent label, or a FRET pair. The claims of the ‘749 patent do not state that the detectable entity is attached to the second binding sequence, but the ordinary artisan would have recognized that the detectable entity could be attached to any portion of the primer-switch recited in the claims of the ‘749 patent (e.g., the second binding sequence). Thus, the instant claims 30, 32, and 33 are not patentably distinct from the claims of the ‘749 patent.
The instant claim 34 depends from the instant claim 33 and requires the detectable entity to be unquenched during extension of the forward primer. The claims of the ‘749 patent suggest that the primer-switch contains a FRET pair (see claim 10). The ordinary artisan would have recognized that for a FRET pair to be a useful label, a signal change (i.e., quenching or unquenching) upon hybridization and/or extension of the forward primer must occur for the label to be useful. Accordingly, unquenching upon extension would have been considered an obvious option, and the instant claim 34 is not patentably distinct from the claims of the ‘749 patent.
The instant claim 35 depends from the instant claim 26 and states that the first and second binding sequences are not attached to a solid support. This requirement is suggested by claims 1 and 16 of the ‘749 patent, which do not require the primer-switch oligonucleotide to be attached to a solid support.
The instant claim 36 depends from the instant claim 26 and requires the composition to further include a reverse primer. This is suggested by claim 16 of the ‘749 patent because that claim is drawn to a kit that comprises an oligonucleotide with all of the features required by the instant claim 26 and also a reverse primer. The ordinary artisan would have recognized that one use for a kit comprising a reverse primer and an oligonucleotide containing a forward primer is formation of a composition containing both oligonucleotides (e.g., to conduct an amplification reaction). Thus, the instant claim 36 is not patentably distinct from the claims of the ‘749 patent.
The limitations of the instant claim 43, which depends from the instant claim 26, are recited in claim 6 of the ‘749 patent.
The limitations of the instant claim 44, which depends from the instant claim 26, are recited in claim 7 of the ‘749 patent.
The limitations of the instant claim 45, which depends from the instant claim 26, are recited in claims 6 and 7 of the ‘749 patent.
The limitations of the instant claim 46, which depends from the instant claim 26, are recited in claims 1, 4-7, and 16 of the ‘749 patent. More specifically, by teaching that the forward primer and second binding sequence target an overlapping sequence (claims 1, 5-7, and 16), which may be 10, 15, or more than 15 nucleotides in length (claim 4), the claims of the ‘749 patent indicate that the forward primer and second binding sequence compete for hybridizing, fully or partially, to the target region sequence.
The limitations of the instant claims 47 and 48, each of which depends from the instant claim 46, are also recited in claims 1, 5, 7, and 16 of the ‘749 patent. As discussed above, these claims in the ‘749 patent indicate that the forward primer and second binding sequence compete for hybridizing, fully or partially, to the target region sequence. As well, claim 7 of the ‘749 patent states that the forward primer may be fully complementary to the wild-type nucleic acid whereas the second binding sequence is fully complementary to the variant nucleic acid. In this embodiment, the forward primer and second binding sequence compete for hybridizing, fully or partially, to the target region sequence that does not contain the nucleic acid variant.
The limitations of the instant claims 48 and 49, which depend from the instant claims 46 and 26, respectively, are recited in claims 1, 4-7, and 16 of the ‘749 patent.
Thus, the instant claims 26, 27, 29, 30, 32-36, and 43-49 are not patentably distinct from claims 1-12 and 16 of the ‘749 patent.
Conclusion
19. No claims are currently allowable.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1637
1 Claim 30 requires a detectable entity to be attached to the second binding sequence.
2 The Ward, Wittwer, and Belouchi references are newly cited. The other references, including a machine translation of Ito, were cited previously. The copies of Ito and its machine translation are present in prior-filed Application Serial No. 15/796,982. The citations to Ito below refer to the machine translation.
3 Satterfield was cited previously. Also, in view of the comments in the “Priority” section, this reference qualifies as prior art.
4 Wang, Belouchi, and Wittwer are newly cited. The other references, including a machine translation of Ito, were cited previously. The copies of Ito and its machine translation are present in prior-filed Application Serial No. 15/796,982.
5 The Ward, Wittwer, and Belouchi references are newly cited. The other references, including a machine translation of Ito, were cited previously. The copies of Ito and its machine translation are present in prior-filed Application Serial No. 15/796,982. The citations to Ito below refer to the machine translation.
6 The ‘749 patent was cited on an IDS.
Prosecution Insights