DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “mixture comprising forward and reverse region primers for an unmethylated …(SNRPN) promoter region in amounts of 400 to 1000 nm, and forward and reverse region primers for a methylated SNRPN promoter region in amounts of 100 to 500 nM.” Claim 4 recites “the forward and reverse region primers for the unmethylated SNRPN promoter region are both in amounts of 1000 nM, and the forward and reverse region primers for the methylated SNRPN promoter region are in amounts of 100 nM and 500 nM, respectively.” (emphasis added). Based on the language in these claims, it is not clear what the amount of primer for the method is added. It is not clear if the primers all have different amounts, if the recited values are a combined amount, or if they have the same amount.
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.
Claims 2, 8, 9-12, 15, and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 recites extracting the DNA from the dried blood sample. This claim is not further limiting because in order to provide DNA from a dried blood sample in claim 1, it would have to be extracted from the sample.
Claims 8, 9, and 11 recite results of the method in claim 1 and do not recite a further active method step.
Claim 10 and 12 recite alternative primers sets from claim 1 and therefore do not require the primer sets recited in claim 1. Therefore, because the claims do not require the limitations of claim 1 they do not further limit claim 1. Claims 15 and 16 depend from claims 10 and 12.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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 1-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon and an abstract idea) without significantly more. The claim(s) recite(s) a method of determining a methylation pattern for a disease state. This judicial exception is not integrated into a practical application based on the reasoning below:
The unpatentability of laws of nature and abstract ideas was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S._,_(2010) (slip op., at 5). “Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U. S. 63, 67 (1972).
Additionally, the unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Inti, 134 S. Ct. 2347, 2354 (2014).
The following inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes, the claims are directed to methods.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes, where the claims recite a step of determining DNA methylation patterns (e.g., claims 1, 10, and 12), determining a disease state (e.g., claims 8-16), such concepts are abstract ideas; they encompass the mental comparison of data and the correlation of data and information to reach a conclusion.
Step 2A, prong 2. Does the claim recite additional elements that integrate the exception into a practical application? No, the judicial exceptions to which the claims are directed are not integrated into a practical application because the rejected claims do not require any particular practical steps related to the detecting DNA methylation that are not considered routine.
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No, the claims include practical steps related to the measuring of DNA methylation, but the broadly recited steps are properly considered routine and conventional and the claims are not significantly more than the judicial exceptions to which they are directed. Where the claims recite limitations of measuring DNA methylation or converting unmethylated cytosines to uracils (e.g., claim 1), performing nucleic acid sequencing (e.g., claim 1, 10, and 12), these steps are regularly found in the art (e.g., Kosaki at al. pages 309-310; Mahmoud et al. pages 3-4; Wojdacz and Dobrovic, see entire document).
The claims that recite “treating the human subject” do not overcome the rejection because providing an instruction to treat a subject without providing a specific treatment, is extra-solution.
For these reasons, the claims are rejected under USC 35 section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-9, 11, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Kosaki et al. (American Journal of Medical Genetics, 1997), Ferreira et al. (Scientific Reports, 2020), Wojdacz and Dobrovic (DNA Methylation: Methods and Protocols, 2009), and Kubota et al. (Nature Genetics, 1997).
Kosaki et al. teach a method of diagnosing Prader-Willi and Angelman syndromes with a bisulfite-treated methylation-specific PCR method. Kosaki et al. teach using genomic DNA from subjects and treating them with sodium bisulfite. (pages 309-310). Kosaki et al. teach amplifying the DNA in an amplification mixture comprising forward and reverse primers for both unmethylated and methylated SNRPN region. (page 310).
Kosaki et al. teach the following amplification parameters:
Initial denaturation at 94°C; and
a total of 35 cycles of: 94°C, 63°C, 72°C.
Kosaki et al. teach the use of primers that match SEQ ID NOs: 6, 7, 8, and 9. (see Table 1). SEQ ID NO: 6 matches UNMET forward primer, SEQ ID NOs: 7 and 9 match UNMET reverse primer, and SEQ ID NO: 8 matches MET forward primer. (Table 1). Kosaki et al. teaches adding the primers at a 40 pmol concentration and the use of dNTPs, not dUTP (page 310).
Kosaki et al. teach analyzing the amplified samples through gel electrophoresis with a larger band at approximately 164bp (unmethylated) and a smaller band at approximately 131bp (methylated). (figure 3).
Ferreira et al. teach a method of screening for Prader-Willi syndrome. Ferreira et al. teach that DNA samples from newborns were collected and placed on newborn screening filter paper cards. (page 6). Ferreira et al. teach DNA was extracted from the dried blood spots on the filter paper and treated with sodium bisulfite. (page 6-7). Ferreira et al. teach amplifying the sample. (page 7).
Wojdacz and Dobrovic teach DNA methylation analysis followed by a melting curve assay resulting in highly sensitive detection of low-level methylation. Wojdacz and Dobrovic teach treating DNA with sodium bisulfite to chemically modify unmethylated cytosines to uracil. (page 232-3). Wojdacz and Dobrovic teach PCR amplification, with standard dNTPS, of the treated DNA under the following parameters:
Initial activation at 95°C;
50 cycles at 95°C, 63°C, and 72°C;
Followed by denaturing at 95°C, re-annealing by fast cooling, then holding at 75°C;
With the melting curve analysis done at 70-95°C.
Kubota et al. teach a methylation specific PCR method to determine if a subject has Prader-Willi syndrome or Angelman syndrome. Kubota et al. teach a multiplex PCR with two primer sets, one for unmethylated DNA and one for methylated DNA. (Figure 1). Kubota et al. teach that the unmethylated PCR primers are added at 1.2 µM and the methylated at 0.4 µM. (figure 1). Kubota teach the following PCR parameters:
Initial activation at 95°C;
35 cycles at 94°C, 62°C, and 72°C.
Based on the above disclosures, one of ordinary skill in the art would be motivated to screen newborn human babies for Prader-Willi syndrome or Angelman Syndrome using a methylation PCR method that detects an unmethylated and methylated band in the samples because the techniques were known in the art as were the specific primers recited in claim 1. They would further be motivated to perform a melting curve analysis to determine the sensitivity of the assay to ensure an accurate assessment of the methylation status. Regarding the PCR parameters in claim 1, as shown above, one of skill in the art would be motivated to optimize the PCR parameters for the specific conditions, samples, and primers. Each method recited uses slightly different parameters with slightly different DNA sample amounts, and primers. One of skill in the art understands that PCR conditions are based on these factors and would make the required adjustments to achieve optimal results. Regarding the PCR primer amounts recited in claim 1 and 4, the prior art teaches an optimization based on DNA amount in the sample. For example, Kosaki et al. teach using 40 pmol of primer with a DNA sample that at most is 0.1 ng of DNA. (page 309-310). Kubota et al. teach using a ratio of primers at 1.2M to 0.4M with 30 ng of DNA sample. (page 16). Therefore, one of ordinary skill in the art would modify the amount of primer used based on the amount of DNA sample used.
Regarding claims 2 and 7, Ferreira et al. teach using a dried blood sample human newborn babies. (page 6).
Regarding claim 3, Ferreira et al. teach that the dried blood samples are collected on Guthrie cards and the samples are used for newborn screening programs that identify inherited diseases, avoiding morbidity, and mortality associated with genetic disorders. (page 2). Therefore, because the sample is extracted for all newborn screening, it satisfies the limitations of the claim.
Regarding claims 5 and 6, the instant specification describes a high-throughput assay as a 96-well plate setting. (page 3). Ferreira et al. teach the use of a 96-well plate to perform the analysis. (page 7).
Regarding claim 8, Kosaki et al. teach that both methylated and unmethylated alleles indicates a normal sample. (figure 3).
Regarding claims 9 and 13, Kosaki et al. teach that only unmethylated alleles indicate Angelman syndrome. (figure 3). Ferreira et al. teach that Angelman syndrome has a host of features such delayed psychomotor development, severe mental retardation, absence of speech, seizures, motor oddities, and epilepsy that one of ordinary skill in the art would be motivated to treat after confirmation of a positive diagnosis.
Regarding claims 11 and 14, Kosaki et al. teach that only methylated alleles indicate Prader-Willi syndrome. (figure 3). Ferreira et al. teach that Prader-Willi syndrome a host of features as recited on page 1 that one of ordinary skill in the art would be motivated to treat after confirmation of a positive diagnosis.
Claim(s) 10, 12, 15, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kosaki et al. (American Journal of Medical Genetics, 1997), Ferreira et al. (Scientific Reports, 2020), Wojdacz and Dobrovic (DNA Methylation: Methods and Protocols, 2009), and Kubota et al. (Nature Genetics, 1997) as applied to claims 1-9, 11, 13, and 14 above, and further in view of Askree et al. (Journal of Molecular Diagnostics, 2011).
The teachings of Kosaki et al., Ferreira et al., Wojdacz and Dobrovic, and Kubota et al. are applied to claims 10, 12, 15, and 16 as applied to claims 1-9, 11, 13, and 14 above. These do not teach the alternative primers in claims 10 and 12 and the corresponding gel electrophoresis bands at 152 bp and 92 bp.
Askree et al. teach a methylation sensitive PCR to test for Prader-Willi syndrome and Angelman syndrome. (abstract). Askree et al. teach bisulfite conversion followed by PCR with alternate methylated and unmethylated primer sets that match SEQ ID NOs: 10-13. (page 110, top right column). Askree et al. teach the alternate primers amplify a 152 bp fragment and a 92 bp fragment. Askree et al. teach that the 152 bp fragment is indicative of Prader-Willi syndrome (lane 6) and the 92 bp fragment is indicative of Angelman syndrome (lane 7). (figure B, bottom panel).
Askree et al. teach these alternative primers because commonly used metylation specific PCR assays can create false-positives due to allelic dropout. (abstract). Askree et al. developed the alternative primers to confirm a positive diagnosis by analyzing an additional site. (page 110).
Therefore, one of ordinary skill in the art would add the additional primers taught by Askree et al. to the method taught by Kosaki et al., Ferreira, Wojdacz and Dobrovic, and Kubota et al. for additional confirmation of a positive diagnosis of two syndromes with multiple features. Furthermore, in regard to claims 15 and 16, one of ordinary skill in the art would be motivated to treat after confirmation of a positive diagnosis.
Conclusion
No claims are allowed.
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/MINDY G BROWN/ Patent Examiner, Art Unit 1683 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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