Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s remarks filed demonstrating basis in provisional 62/358,701 are persuasive. The filing date for these claims is the provisional filing date 7/6/2016.
DETAILED ACTION
Election/Restriction
Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 90-98, 102-106 and 108-116, drawn to a method for classifying an esophageal sample as a methylated sample, classified in C12Q 1/6886.
II. Claim 117, drawn to a computer implemented method using a previously generated classifier, classified in G16B 20/00.
The inventions are independent or distinct, each from the other because:
Inventions I and II are directed to related methods. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed they have a materially different function and effect; one method includes steps of carrying out biochemical processes and analysis while one relies entirely on previously gathered data and data classification. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
(a) the inventions have acquired a separate status in the art in view of their different classification;
(b) the inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries);
(c) the inventions are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Newly submitted claim 117 directed to an invention that is independent or distinct from the invention originally claimed for the given above.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 117 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Rejections - 35 USC § 101
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 90-98, 102-106 and 108-116 are rejected under 35 U.S.C. 101 because the invention is drawn towards methods that recite abstract ideas and laws of nature without significantly more.
The claims are drawn to methods.
Each independent claim recites “measuring the number of methylated cytosines of the CpG dinucleotides,” and “calculating percentage of total reads are methylated” which, when read in light of the specification, reasonably read on reviewing data and analyzing it to count CpG (a mental process), calculating the percentage of methylated CpG within a read (a mathematical calculation), counting the number of methylated reads in a sample and calculating the percentage of methylated reads (a mathematical calculation). These steps, considering the broadest reasonable interpretation of the claims encompass the review and analysis of data, which is simple enough to be performed in the mind and thus the claims set forth abstract ideas that are mental processes, and in the case of calculating percentages are also mathematical concepts that are calculations.
Claims 111-116 set forth a relationship between the percentage of methylated vimentin sequences in a sample and the presence of esophageal neoplasia or metaplasia. This describes a naturally occurring correlation that the courts have recognized as a natural law.
In addition to the judicial exceptions, claims 90 and 105 recite providing a sample, treating with bisulfite and amplifying the plurality of bisulfite converted nucleic acids using primers comprising SEQ ID NO: 16209 and 16210. These steps are pre-solution activity recited at a high level of generality and do not apply or use the judicial exception in any way. Therefore, they do not integrate the judicial exceptions.
In addition to the judicial exceptions, claim 111 recites providing a sample, treating with bisulfite, amplifying the plurality of bisulfite converted nucleic acids, and administering an endoscopy to the subject. These steps are extra-solution activity recited at a high level of generality and do not apply or use the judicial exception in any way. Therefore, they do not integrate the judicial exceptions. The “performing endoscopy” step does not require any treatment element, and is an additional step of mere data gathering.
The additional steps in claims 90 and 105 are not enough to amount to significantly more than the judicial exception because the providing a sample, bisulfite treating and amplifying are recited at such a high level of generality that they amount to insignificant presolution activity. Further, sequencing a portion of the vimentin gene amplified with the recited primers and comprising the recited nucleic acid sequences does not represent an inventive concept since this technique has been known since at least 2009, See Li et al. The disclosed individual primers are both bisulfite specific and methylation specific. The group of primers used together by Li et al. are methylation indifferent. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because these presolution activities were well known, routinely practiced techniques at the time of the invention, see the review article Lee et al. (Cancer Lett. 2013 November 1; 340(2): doi:10.1016/j.canlet.2012.10.040. sixteen pages) which teaches a variety of next-generation sequencing techniques. The reference teaches bisulfite treatment followed by next-generation sequencing including PCR amplification steps for the analysis of methylation in obtained biological samples, which includes determining the methylated cytosines in an amplified portion of a target.
Further, the “administering an endoscopy” step in claim 111 is post solution activity that amounts to additional data gathering. Data gathering cannot make an otherwise non statutory claim statutory, see MPEP 2106.05(c). Furthermore, well before the invention was made, Jin et al. taught following a methylation based diagnostic screening with endoscopy surveillance (throughout, Jin et al. Cancer Res 2009; 69: (10). May 15, 2009).
The steps in claims 91, 94, 106, 112 are insignificant extra-solution activity, and the limitations do not impose meaningful limits on the claims. These steps are recited at a high level of generality such that it amounts to insignificant pre-solution activity. Further, next-generation sequencing of bisulfite treated nucleic acids was a well-known technique, as discussed previously.
The limitations in claims 102-104, 108-110 and 114-116 do not add any further process step and thus the analysis for the independent claims apply to these claims.
Claims 92-93 recites that the esophageal sample is obtained by cytology brushing or by balloon. This is presoultion activity that does not integrate the exceptions. Further it does not amount to significantly more because it is presolution activity recited at a high level of generality and obtaining tissue samples by brushing and by means of a balloon were techniques routinely used in medicine at the time of the invention (as discussed in Koss et al. (Am J Clin Pathol 1998; 109:549-557)).
Claims 95 recites the use of “methylation specific” primers which do not integrate the judicial exceptions by applying them in any way, and further which does not provide an advance over the prior art at least as supported by Markowitz et al. which teaches methylation specific primers were routine (¶0163).
Claims 98 further defines the mental process of reviewing data resulting from sequencing. It does not integrate the judicial exception or amount to significantly more following the reasoning applied to the independent claim.
Accordingly, the claims are directed to judicial exceptions.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 90- 92, 94- 98, 102-104, 105-106, and 108-110 is/are rejected under 35 U.S.C. 103 as being unpatentable Markowitz et al. (US 2012/0094287) in view of Zhang et al. (US 20160210403), Redshaw et al. (BMC Genomics 2014, 15:1174, 14 pages) and Li et al. (Nature Biotechnology, Vol 27, Number 9, September 2009, pages 858-863, including online methods).
Markowitz teaches a method for assaying methylation that includes providing an esophageal sample obtained from a subject, treating with bisulfite and then amplifying the plurality of bisulfite converted vimentin nucleic acid sequences using PCR to generate an amplified portion for each bisulfite converted vimentin sequence (disclosed therein as SEQ ID NO: 2; see Example 3). The claim limitation “wherein each amplicon is a read” does not modify the action of the amplifying, it merely assigns a name to the “amplicons.”
Markowitz et al. teach detecting vimentin methylation (See Example 3 and Figure 55).
Markowitz et al. teach that amplification can occur using methylation-sensitive primers (¶ 0007, ¶109).
The reference teaches most esophageal adenocarcinoma samples showed high levels of vimentin methylation, from 10% to 100% of total input tumor DNA (Fig 51), and also that methylation as low as 1% of total input tumor DNA was observed (¶ 0253).
Markowitz teaches a differentially methylated region within the vimentin gene (see Figures 22-26). This region includes more than ten CpG.
The reference does not teach measuring the number of methylated CpG dinucleotides in an amplified portion of the bisulfite converted vimentin nucleic acid sequence and the reference does not teach counting or measuring the number of methylated reads when they are present. The reference teaches that methylated positions could be identified by directly sequencing amplification products to determine CpG or UpG dinucleotides (¶ 0176). The reference does not teach employing next-generating sequencing.
Zhang teaches analysis of methylation for the detection of cancer. The reference teaches a methylation profile that is a set of data represent methylation states of levels of one or mor biomarker or loci within a molecule of DNA. See para 165. The reference teaches methylation data includes a methylation density of CpG sites in a region, a distribution of CpG sites over a region, a pattern or level of methylation for one or more individual CpG sites within a region that contains more than one CpG sites. See para 165. The reference teaches the methylation status can indicate information regarding regional methylation density within a sequence without providing precise information where in the sequence the methylation occurs. See para 172.
The reference teaches the methylation density is the number of reads at sites within the region showing methylation divided by the total number of reads covering the sites in the region. CpG methylation density of a region is the number of reads showing CpG methylation divided by the total number of reads covering CpG sites in the region. See para 174.
The reference exemplifies generating sequencing reads by bisulfite converting DNA, PCR amplifying the DNA and then sequencing the resultant libraries. See page 42. Para 429, 434.
The reference does not provide any details or specifics about how to “call “a read as “showing CpG” methylation, or as a methylated read.
Redshaw et al. teach employing bisulfite amplicon next generation sequencing to detect methylated CpG positions (p. 12), and the reference teaches obtaining an amplicon having 19 informative sites and producing a read based estimate in which each sequence read was considered methylated when greater than 80% of the interrogated positions were unconverted (i.e. methylated) (p. 12). These reads are analogous to the “reads showing methylation” as taught by Zhang et al. Thus, Redshaw et al. teaches a method which includes measuring the number of methylated cytosines in an amplified portion of a bisulfite converted nucleic acid sequence, wherein a methylated read is identified when at least 80% of the cytosines in the CpG dinucleotides of the individual amplified portion of the bisulfite converted sequence is methylated, and measuring the number of reads and the number of methylated reads present in the sample.
It would have been prima facie obvious to one having ordinary skill in the art at before the effective filing date to have modified the method taught by Markowitz et al. so as to have employed the methods taught by Zhang which teach sequencing to detect methylation in nucleic acid sequences and to analyze reads using the sequencing method. It would have been obvious to have calculated the methylation density of a region by determining the number of methylated reads and dividing that by the total number of reads. One would have been motivated to do so by the teachings of Zhang et al. that this is one way to present a methylation profile useful for detecting cancer. Furthermore, it would have been obvious to have used the method taught by Redshaw to determine which reads are methylated, as this was a known technique that could be applied for its intended purpose. The combined method results in identifying a read as methylated if at least 80% of the cytosines in CpG dinucleotides are methylated. Furthermore, given that Markowitz et al. teach that total methylation in EAC varied from 1%-100%, it would have been prima facie obvious to one having ordinary skill in the art to have determined that a sample was methylated when greater than 1% of the reads were identified as methylated, and when greater than 1.05% of the reads are methylated, when greater than 3% of the reads are methylated, and also when greater than 5% of the reads are methylated (see Markowitz Figure 51). This reads on an embodiment of the range “wherein at least 0.95% of the reads are methylated” since 1% is “at least” 0.95%. Further still, the “whereby” clause is not an active step of classifying, and sets forth what appears to be an inherent or necessary outcome of the measuring the number of reads and the number of methylated reads present in the sample.
With regard to claims 102-104 and 108-110, samples taught by Markowitz et al. that have 100% total methylation and are from carcinoma cases inherently would have the required number of minimum reads.
Markowitz in view of Redshaw do not teach the primers required by claims 90 or 105.
These primers are identical to the primers taught by Li et al. for the amplification of a region of vimentin, a region which is within the DMR taught by Markowitz. See online methods, section “PCR amplification of bisulfite-converted DNA.” Li et al. teach amplification with a combination of two forward primers and two reverse primers. Each of these individual primers is methylation specific and bisulfite specific. Taken together as a group, the “primers” are methylation indifferent and bisulfite specific. The primers are methylation indifferent as a group because the group of primers would amplify the bisulfite products from both methylated and unmethylated original targets.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date to have employed the amplification primers of Vogelstein within the method by Markowitz in view of Redshaw in order to provide an amplification product for determining methylation levels and diagnosing and treating esophageal metaplasia or neoplasia.
Regarding claims 105-106 and 108-110, Markowitz teaches that the detection of methylation (i.e. production of a methylation specific PCR product) indicates that the subject has cancer or pre-cancerous adenomas (¶7, claims, throughout). Furthermore, the “whereby” clause in claim 105 recites an inherent property that flows naturally from the practice of the method steps. It does not require any further action other than the providing, amplifying, measuring and calculating steps set forth in the claims and addressed by the references.
Claims 111-116 is/are rejected under 35 U.S.C. 103 as being unpatentable Markowitz et al. (US 2012/0094287) in view of Zhang et al. (US 20160210403), Redshaw et al. (BMC Genomics 2014, 15:1174, 14 pages) and Shah et al. (J Gastrointest Oncol 2015;6(1):20-30).
Markowitz et al. teaches a method for detecting neoplasia of the upper gastrointestinal tract comprising obtaining a human sample and assaying said sample for the presence of methylation within the vimentin gene (disclosed therein as SEQ ID NO: 2), wherein methylation of said nucleotide sequence is indicative of neoplasia of the upper gastrointestinal tract, and in particular esophageal cancer (see Markowitz claim 7). Thus, the reference teaches diagnosing a subject as having an esophageal neoplasia or metaplasia following measuring methylation in the vimentin gene. Markowitz teaches that the subject is known to have or suspected of having cancer (¶ 0009).
Markowitz teaches a method for assaying methylation that includes providing an esophageal sample obtained from a subject, treating with bisulfite and then amplifying the plurality of bisulfite converted vimentin nucleic acid sequences to generate an amplified portion for each bisulfite converted vimentin sequence (see Example 3). The claim limitation “wherein each amplified portion is a read” does not modify the action of the amplifying, it merely assigns a name to the “amplified portions.”
The reference teaches most esophageal adenocarcinoma samples showed high levels of vimentin methylation, from 10% to 100% of total input tumor DNA (Fig 51), and also that methylation as low as 1% of total input tumor DNA was observed (¶ 0253).
Markowitz teaches a differentially methylated region within the vimentin gene (see Figures 22-26). This region includes more than ten CpG.
The reference does not teach measuring the number of methylated CpG dinucleotides in an amplified portion of the bisulfite converted vimentin nucleic acid sequence and the reference does not teach counting or measuring the number of methylated reads when they are present. The reference teaches that methylated positions could be identified by directly sequencing amplification products to determine CpG or UpG dinucleotides (¶ 0176). The reference does not teach employing next-generating sequencing.
Zhang teaches analysis of methylation for the detection of cancer. The reference teaches a methylation profile that is a set of data represent methylation states of levels of one or mor biomarker or loci within a molecule of DNA. See para 165. The reference teaches methylation data includes a methylation density of CpG sites in a region, a distribution of CpG sites over a region, a pattern or level of methylation for one or more individual CpG sites within a region that contains more than one CpG sites. See para 165. The reference teaches the methylation status can indicate information regarding regional methylation density within a sequence without providing precise information where in the sequence the methylation occurs. See para 172.
The reference teaches the methylation density is the number of reads at sites within the region showing methylation divided by the total number of reads covering the sites in the region. CpG methylation density of a region is the number of reads showing CpG methylation divided by the total number of reads covering CpG sites in the region. See para 174.
The reference exemplifies generating sequencing reads by bisulfite converting DNA, PCR amplifying the DNA and then sequencing the resultant libraries. See page 42. Para 429, 434.
The reference does not provide any details or specifics about how to “call “a read as “showing CpG” methylation, or as a methylated read.
Redshaw et al. teach employing bisulfite amplicon next generation sequencing to detect methylated CpG positions (p. 12), and the reference teaches obtaining an amplicon having 19 informative sites and producing a read based estimate in which each sequence read was considered methylated when greater than 80% of the interrogated positions were unconverted (i.e. methylated) (p. 12). These reads are analogous to the “reads showing methylation” as taught by Zhang et al. Thus, Redshaw et al. teaches a method which includes measuring the number of methylated cytosines in an amplified portion of a bisulfite converted nucleic acid sequence, wherein a methylated read is identified when at least 80% of the cytosines in the CpG dinucleotides of the individual amplified portion of the bisulfite converted sequence is methylated, and measuring the number of reads and the number of methylated reads present in the sample.
It would have been prima facie obvious to one having ordinary skill in the art at before the effective filing date to have modified the method taught by Markowitz et al. so as to have employed the methods taught by Zhang which teach sequencing to detect methylation in nucleic acid sequences and to analyze reads using the sequencing method. It would have been obvious to have calculated the methylation density of a region by determining the number of methylated reads and dividing that by the total number of reads. One would have been motivated to do so by the teachings of Zhang et al. that this is one way to present a methylation profile useful for detecting cancer. Furthermore, it would have been obvious to have used the method taught by Redshaw to determine which reads are methylated, as this was a known technique that could be applied for its intended purpose. The combined method results in identifying a read as methylated if at least 80% of the cytosines in CpG dinucleotides are methylated. Furthermore, given that Markowitz et al. teach that total methylation in EAC varied from 1%-100%, it would have been prima facie obvious to one having ordinary skill in the art to have determined that a sample was methylated when greater than 1% of the reads were identified as methylated, and when greater than 1.05% of the reads are methylated, when greater than 3% of the reads are methylated, and also when greater than 5% of the reads are methylated (see Markowitz Figure 51). This reads on an embodiment of the range “wherein at least 0.95% of the reads are methylated” since 1% is “at least” 0.95%. Further still, the “whereby” clause is not an active step of classifying, and sets forth what appears to be an inherent or necessary outcome of the measuring the number of reads and the number of methylated reads present in the sample.
Markowitz et al. in view of Redshaw et al. do not teach administering an endoscopy to the subject with a methylated sample.
Shah et al. teach that treatment options for esophageal metaplasia and neoplasia include a combination of endoscopic treatment (i.e. endoscopy), chemotherapy, radiation therapy and surgical resection (p. 21).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date to have included a step of treating the identified metaplasia or neoplasia by employing the endoscopic treatment taught by Shan et al. in order to restore the patient to health.
Claim 93 is/are rejected under 35 U.S.C. 103 as being unpatentable over Markowitz et al. (US 2012/0094287) in view of Redshaw et al. (BMC Genomics 2014, 15:1174, 14 pages) and Li et al. (Nature Biotechnology, Vol 27, Number 9, September 2009, pages 858-863, including online methods) as applied to claims 90, 91, 92, 94, 95, 98, 99, and 101-104 above, and further in view of Koss et al. (Am J Clin Pathol 1998; 109:549-557).
The teachings of Markowitz et al. in view of Redshaw et al. are given previously in this Office action and fully incorporated here. Markowitz et al. teach detecting vimentin methylation in brushings as indicative of metaplasia or neoplasia (See Example 3 and Figure 55). The references do not teach a method wherein the brushing is by means of a balloon.
Koss teaches obtaining tissue samples from patients at risk for esophageal carcinoma using the esophageal balloon technique.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date to have modified the method taught by Markowitz et al. in view of Redshaw et al. so as to have used the esophageal balloon technique as the substitution of one known method for obtaining esophageal cells for analysis for another to achieve the predictable result of obtaining esophageal cells for methylation analysis.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The 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.
Claims 90-98, 102-106 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11136629, 10450615, 8415100, 8221977, each of these patents and applications in view of Markowitz (US PGPUB 2012/0094287) and Zhang, Redshaw and Shah and Li et al. and Koss.
The issued patents and copending applications claim products and methods for detecting esophageal cancer by detecting methylation in vimentin.
These do not teach the measuring steps required by the instant claims or the cut-offs set forth in the rejected claims. The teachings of the additional references are given previously in this Office action and are incorporated herein. The cutoffs for vimentin are taught by Markowitz in view of Zhang and Redshaw. It would have been obvious to have modified the methods claimed in the issued patents so as to have applied the methylation analysis and cut-off levels taught in the prior art in order to provide a method with high specificity and sensitivity for the detection of esophageal metaplasia and dysplasia.
Furthermore, insofar as these to not teach treating conducting an endoscopy, the reasons this would be further obvious in view of Shah apply here and are fully incorporated.
Furthermore, insofar as these do not teach employing the primers of claims 90 and 105 the reasons this would be further obvious in view of Li et al. apply here and are fully incorporated.
Furthermore, insofar as these do not teach using a balloon to obtain an esophageal sample, the reasons this would be further obvious in view of Koss apply here and are fully incorporated.
Response to Remarks
Applicant’s comments on “the claimed subject matter” are noted. The response emphasizes that “sequences between the primers” and not “under the primers” are interrogated, but this is not claim limitation. The claims are of sufficient breadth so as to consider sequences under the primers, and in fact appear to require as much since the number of methylated cytosines “in each amplicon” are measured, and there is no mention in the claims that the measuring the number should exclude the CpG that are “under” the primers. Both SEQ ID NO: 16209 and 16210 are themselves degenerate primers that overlap with CpG or the complement (or bisulfite converted version) thereof.
Regarding the rejection under 101, applicant traverses.
Apoplicant argues that in the context of the claimed invention, the use of the claimed primer sequences to provide the vimentin amplicon is inventive obtaining the number of methylated cytosines. However, the “obtaining the number of methylated cytosines in each amplicon” is a judicial exception. The claims do not recite the step of sequencing the amplicons, per se, though it is implied, the claim omits that step and directs to the counting of CpG in each read to classify it, which is an abstract idea. The only manipulative step steps in the claim 90 (i.e. in addition to the judicial exceptions) are the providing and amplifying steps. Applicant is arguing features that are not claimed. Where the additional step requires amplifying with the recited primers, this was known. The setting of a cut-off etc, argues at the top of page 9 of the response argues to the judicial exceptions, not to integration or to any method steps that amount to significantly more than the judicial exceptions.
With regard to claim 111, applicant argues that classifying a sample as methylated is based on a product of human design (the disclosed cutoff) and not a law of nature. However, the relationship between the presence of methylation and esophageal cancer is a naturally occurring relationship. Furthermore, regardless of the natural law judicial exception, the claim persists in reciting the mental process judicial exceptions noted in the claim.
Applicant argues that the mental process in the claims (counting CpG) cannot reasonably occur in the mind but provides on explanation or evidence as to why one could not review sequencing results and for each read count the number of methylated positions. Further, there is no requirement that mathematical concept abstract ideas be capable of being carried out in the mind to be considered judicial exceptions.
The rejection is maintained.
Applicant traverses the rejections for obviousness.
Applicant points out that Markowitz teaches methylation specific amplification, and not the analysis method of the claimed invention. This is a piecemeal analysis. Critical to the obviousness rejection, Markowitz et al. teaches that the Vimenten gene is differentially methylated in esophageal cancer, teaching that esophageal adenocarcinoma showed from 1% to 100% of total input tumor DNA was methylated. See Fig 51 and ¶253.
Applicant argues that the teaching of Zhang is general and high level, and that ”it is not possible to understand the teaching of the reference alone or in combination with Markowitz.” Zhang discusses different ways of analyzing bisulfite sequencing data for detecting methylation in samples, including, for determining methylation that is related to the presence of cancer. The reference teaches determining the density of methylation in a target region by calculating the number of reads of the region having methylation by the total number of reads in the region. See ¶174. Contrary to applicant’s argument, it is apparent that Zhang is in a similar field of endeavor as Markowitz, that is directed towards ways to use methylated regions, and data derived therefrom for the diagnosis and understanding of cancer.
Applicant argues that the teaching of Zhang “alone, or even in the context of Markowitz et al., is meaningless and irrelevant to the specific claim elements of the pending claims.” This is a piecemeal analysis that does not consider the totality of the rejection, which also includes Li et al. and Redshaw et al.
Applicant argues that Li et al.’s disclosure is unrelated to the claimed methods since they employ a different methodology. However, Li et al. provide primers for amplification of cancer-associated methylated region of vimentin. It is entirely relevant teaching, and provided an art recognized technique for amplifying vimentin for methylation analysis.
An updated declaration is provided and is considered. See declaration filed 3/30/2026. The remarks state that neither Zhang nor Redshaw teach the cutoff of at least 0.95% total reads are methylated reads. However, as the rejection states, given that Markowitz et al. teach that total methylation in esophageal cancer varied from 1% to 100%, this cutoff is obvious.
The Markowitz declaration 3/3/2026, which is an inventor declaration, has been fully considered but is not persuasive because Zhang teaches calculating a methylation density by dividing the number of methylated reads by the total number of read. Redshaw provides guidance as to how to identify a read as methylated. Therefore, the rejection no longer suggests a method which does not consider indeterminate reads, as Zhang teaches calculating density using the total number of reads. There is no evidence to support any unexpected result that shows that the variation cited in the declaration of the number of indeterminate reads affected the outcome of classifying methylation status of a sample. Furthermore, it is noted that in claim 90 and dependent claims there is no step of diagnosing EAC. There is no showing that the “unexpected” number of indeterminate reads has any practical significance to overcome the prima facie case.
Furthermore, the declaration focuses on one specific amplicon, and does not appear to consider all of the CpG in the amplicon (i.e. excludes those under the primers) and so is not commensurate in scope with the claims, particularly claims 111 and its dependents which do not recite any particular amplicon, only one in vimentin.
Regarding the double patenting rejection, applicant argued that the NDSP rejections fail for the same reasons that the obviousness rejections fail. The examiner cannot agree for the same reasons that the arguments were not persuasive in the obviousness context. The response requests that the Examiner hold the provisional rejection in abeyance until otherwise allowable subject matter is identified in the instant application. However, a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. MPEP §804(I)(b)(1). Therefore, for the reasons set forth above and those already of record, the provisional nonstatutory double patenting rejection is modified to address the amended claims, and maintained.
The rejections for the remaining patents and patent applications are MAINTAINED. Rejections are not held in abeyance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached on (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
Prosecution Insights