DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed March 2, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicant’s election without traverse of Group I in the reply filed on July 29, 2025 is reiterated for the record. Additionally in response to the election of species requirement, the Applicants elected SEQ ID NOs: 17 and 18.
Claims 5, 7-8, 10-11, 13-26 are currently pending.
Claims 8, 10-11, 13, 21-22, and 24-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected subject matter (a non-elected invention), there being no allowable generic or linking claim.
Claim 19 has been examined to the extent that the claims read on the elected primers (SEQ ID NOs: 17 and 18). The additionally recited primer sequences have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 112
3. 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 5, 7, and 17-20 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.
Regarding Claims 5, 7 and 17-20 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method for detecting one or more cancer, yet the method only requires steps of treating DNA with a reagent that modified DNA in a methylation specific manner and detecting a methylation modification of a polynucleotide. Thus it is not clear if applicant intends to cover only a method of treating DNA with a reagent that modified DNA in a methylation specific manner and detecting a methylation modification of a polynucleotide OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
Regarding Claims 5, 7 and 17-20 it is noted that a broad limitation together with a narrow limitation that falls within the 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. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation of treating DNA with “a reagent that modifies DNA in a methylation specific manner”, and the claim also recites DNA treated “with bisulfite” which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 112(a)
4. 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 5, 7 and 17-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of the Claims/Nature of the Invention
Claims 5, 7 and 17-20 are drawn to a method for detecting one or more cancers. The claims state that the one or more cancers are selected from breast cancer, leukemia, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and esophageal cancer.
The claims recite a first step of treating DNA extracted from one or more samples comprising tumor cells with a reagent that modifies DNA in a methylation specific manner. The claims broadly encompass being able to detect the recited cancer types based on the analysis of ANY sample type comprising tumor cells. Claim 7 states that the one or more samples comprise: tissue samples, paraffin embedded samples, blood samples, pleural effusion samples, alveolar lavage fluid samples, ascites and lavage fluid samples, bile samples, stool samples, urine samples, saliva samples, sputum samples, cerebrospinal fluid samples, cell smear samples, cervical scraping or brushing samples, and/or cell biopsy samples.
The claims recite a second step of detecting a methylation modification of a polynucleotide using a tumor detection agent or kit, wherein the polynucleotide is: a fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ IDNO: 17 and SEQ ID NO: 18. In view of the recitation of “methylation modification” the claims broadly encompass ANY type of methylation modification (i.e., 5-methylcytosine, N6-methyladenine, N4-methylcytosine, Non-CpG methylation (CHG or CHH)). Claim 20 states that the modification comprises 5- methylation, 5-hydroxymethylation, 5-formylcytosine or 5-carboxylcytosine.
As discussed above, the claims are drawn to a method for detecting cancer but the claims do not set forth any active process steps of detecting cancer. The claims broadly encompass detecting cancer based on the presence or absence of any methylation modification in the 84 bp fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NO: 17 and 18.
The nature of the invention requires a reliable correlation between the presence or absence of a methylation modification at any of one or more of the bases within the 84 bp fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NO: 17 and 18.
Teachings in the Specification and Examples
The specification (para 0077) teaches that SEQ ID NO: 2 corresponds to chr6:391780-393627/hg19 which has 204 CpG sites. The specification (para 0079) teaches that the bisulfite treated sequence of SEQ ID NO: 2 is shown in SEQ ID NO: 4. The specification (Table 2) teaches that SEQ ID NO: 17 and 18 detect CpG sites 010-015 of SEQ ID NO: 2. The primers amplify nucleotides 107-192 of SEQ ID NO: 4.
The specification (Example 3) teaches that pyrosequencing was used to verify the difference in methylation of STAMP-EP4 between tumor and non-tumor clinical samples. Para cancerous/non-cancer samples were used as the control group, and tumor samples were used as the experimental group. DNA was extracted and treated with bisulfite. PCR primers and pyrosequencing primers were designed according to the characteristics of SEQ ID NO: 2 of STAMP-EP4 sequence. The methylation values of STAMP-EP4 were detected as the methylation values of CpG sites 10-15 of SEQ ID NO: 2. The bisulfite treated samples were used as templates for PCR amplification. Pyrosequencing was then performed to detect the methylation value of each site in the target region and the average methylation value of all sites were calculated as the STAMP-EP4 methylation value in the sample.
The specification (Example 4) teaches that the STAMP-EP4 methylation value between the control group of 5 cases of breast cancer para cancerous clinical samples and the experimental group of 5 cases of breast cancer clinical samples was compared according to the pyrosequencing in Example 3. The result in FIG. 5 shows that, in clinical samples of breast cancer, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of para cancerous tissues.
The specification (Example 5) teaches that the STAMP-EP4 methylation value between the control group of 8 leukemia bone marrow smear clinical samples and the experimental group of 8 non-leukemia bone marrow smear clinical samples was compared according to the pyrosequencing in Example 3. The result in FIG. 6 shows that, in clinical samples of leukemia, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of non-cancer tissues.
The specification (Example 6) teaches that the STAMP-EP4 methylation value was analyzed on the control group of 8 cases of colorectal cancer para cancerous clinical samples and the experimental group of 8 cases of colorectal cancer clinical samples according to the pyrosequencing in Example 3. The result in FIG. 7 shows that, in clinical samples of colorectal cancer, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of para cancerous tissues.
The specification (Example 7) teaches that the STAMP-EP4 methylation value was analyzed on the control group of 8 cases of liver cancer para cancerous clinical samples and the experimental group of 8 cases of liver cancer clinical samples according to the pyrosequencing in Example 3. The result in FIG. 8 shows that, in clinical samples of liver cancer, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of para cancerous tissues.
The specification (Example 8) teaches that the STAMP-EP4 methylation value was analyzed on the control group of 4 cases of lung cancer para cancerous clinical samples and the experimental group of 4 cases of lung cancer clinical samples according to the pyrosequencing in Example 3. The result in FIG. 9 shows that, in clinical samples of lung cancer, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of para cancerous tissues.
The specification (Example 9) teaches that the STAMP-EP4 methylation value was analyzed on the control group of 4 cases of pancreatic cancer para cancerous clinical samples and the experimental group of 4 cases of pancreatic cancer clinical samples according to the pyrosequencing in Example 3. The result in FIG. 10 shows that, in clinical samples of pancreatic cancer, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of para cancerous tissues.
The specification (Example 10) teaches that the STAMP-EP4 methylation value was analyzed on the control group of 10 cases of esophageal cancer para cancerous clinical samples and the experimental group of 10 cases of esophageal cancer clinical samples according to the pyrosequencing in Example 3. The result in FIG. 11 shows that, in clinical samples of esophageal cancer, the methylation value of STAMP-EP4 in the experimental group was significantly higher than that of para cancerous tissues.
State of the Art and the Unpredictability of the Art
While methods of detecting methylation modifications are known in the art, correlating the methylation modifications with the presence of cancer is highly unpredictable. The unpredictability will be discussed below.
Additionally it is highly unpredictable if the results obtained using esophageal, colorectal, liver, pancreatic, breast, lung, and leukemia samples could be extrapolated to ANY sample type encompassed by the claims. As discussed above, claim 7 comprises tissue samples, paraffin embedded samples, blood samples, pleural effusion samples, alveolar lavage fluid samples, ascites and lavage fluid samples, bile samples, stool samples, urine samples, saliva samples, sputum samples, cerebrospinal fluid samples, cell smear samples, cervical scraping or brushing samples, tissue and cell biopsy samples. However there is no analysis in the specification of methylation in most of these sample types. In the absence of evidence to the contrary, it is highly unpredictable if the hypermethylated CpG sites found in one type of cancer i.e., breast cancer will be hypermethylated in other sample types (pleural effusion, alveolar lavage, bile, etc.) obtained from a subject with breast cancer.
Finally it is relevant to point out the claims encompass detecting cancer based on the presence or absence of any type of methylation modification in a fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NO: 17 and SEQ ID NO: 18. In view of the recitation of “methylation modification” the claims broadly encompass ANY type of methylation modification (i.e., 5-methylcytosine, N6-methyladenine, N4-methylcytosine, Non-CpG methylation (CHG or CHH)). Claim 20 states that the modification comprises 5- methylation, 5-hydroxymethylation, 5-formylcytosine or 5-carboxylcytosine. The breadth of the claims is not supported by the teachings in the specification because the specification is limited to 5-methylcytosine occurring at five specific CpG sites in SEQ ID NO: 4. There is no evidence in the specification that any other types of methylation modifications occur in the fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NO: 17 and SEQ ID NO: 18. Even if other types did occur, it is highly unpredictable if it would be correlated with cancer.
Finally the claims are drawn to a method for detecting cancer but the claims do not set forth any active process steps of detecting cancer. The claims broadly encompass detecting cancer based on the presence or absence of any methylation modification in the 84 bp fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NO: 17 and 18. In the instant case the specification does not provide support for this breadth. The specification (Figures 5-11) teaches that CpG sites 10-15 of SEQ ID NO: 2 were hypermethylated in the following cancer types: esophageal, colorectal, liver, pancreatic, breast, lung, and leukemia in comparison to para cancerous or non cancerous samples. Thus the specification only provides enablement for a method of detecting breast cancer when the fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NOs: 17 and 18 is hypermethylated in a sample comprising breast tissue in comparison to the same fragment in a sample comprising non-cancerous breast tissue.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to detect cancer based on detection of any methylation modification in a fragment obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NOs: 17 and 18.
In order to practice the breadth of the claimed invention additional experimentation would need to be conducted. For example, for each of the cancers encompassed by the claims one would have to assay a representative number of different sample types to detect a representative number of different methylation modifications in fragments obtained by amplifying human genomic DNA treated with bisulfite using primers SEQ ID NOs: 17 and 18.
The specification has merely provided an invitation for further experimentation.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusion:
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the guidance presented in the specification and the working examples, the skill of those in the art and the unpredictability of the art, and the quantity of experimentation necessary, it is the conclusion that an undue amount of experimentation would be required to make and use the invention.
Response To Arguments
5. In the response the Applicants traversed the rejection under 35 USC 112(a).
In the response the Applicants argue that claim 5 has been amended to recite that the detected modification is a methylation modification. The amendment has been fully considered but does not overcome the rejection. As explained above the phrase “methylation modification” broadly encompass ANY type of methylation modification (i.e., 5-methylcytosine, N6-methyladenine, N4-methylcytosine, Non-CpG methylation (CHG or CHH)). However in the absence to the evidence it is highly unpredictable if these other types of methylation occur in the claimed region and are correlated with the cancer.
Regarding the breadth of “samples comprising tumor cells”, the Applicants state that
the sample types listed in claim 7 outline a list of potential sample types that could be used to detect the specific subset of cancers in amended claim 5. They argue that "[t]he presence of inoperative embodiments within the scope of a claim does not necessarily render a claim nonenabled." MPEP 2164.08(b). Instead, "[t]he standard is whether a skilled person could determine which embodiments that were conceived, but not yet made, would be inoperative or operative with expenditure of no more effort than is normally required in the art." This argument has been fully considered but is not persuasive. The claims encompass sample types that are entirely unrelated to any of the claimed sample types. For example the claim 7 recites cervical scraping or brushing samples and it is highly unlikely that methylation in this particular sample type could be used to detect any of the cancers (breast cancer, leukemia, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and esophageal cancer) encompassed by the claims. Additionally claim 7 recites urine samples and it is highly unlikely that methylation in this particular sample type could be used to detect any of the cancers (breast cancer, leukemia, colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and esophageal cancer) encompassed by the claims. The rejections are maintained.
6. 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682