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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06 March 2026 has been entered.
Claim Status
3. Claims 1-20 are pending.
Claims 7 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-6 and 9-20 read on the elected invention and have been examined herein.
Maintained / Modified Claim Rejections - 35 USC § 101
4. 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 1-6, 9-13 and 18-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the level of methylation at particular regions of the genome, including the region of the FECH gene (claim 6), and a particular erythroid cell lineage. Note that the claims recite a final step of “estimating the amount of cells of the particular erythroid cell lineage in the biological sample based on the comparing” of the methylation levels. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
As stated in MPEP 2106.04(a)(2) III “the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.”
The claims require performing the step of “obtaining” calibration data points, “comparing” methylation levels and “estimating” the amount of cells of a particular cell lineage (claim 1); “identifying” a methylation region by “obtaining methylation indexes,” “comparing” methylation indexes, “identifying” sites that have methylation indexes above or below a threshold and “identifying” one or more differentially-methylated regions (claim 10); “determining” a total number and a first methylation level (claim 11); “determining” a volume and a first methylation level (claim 12); and “inputting” a first methylation level into a calibration function (claim 18). Neither the specification nor the claims set forth a limiting definition for the “obtaining,” “comparing,” “estimating,” identifying,” "determining," or “inputting” steps and the claims do not set forth how these steps are accomplished. The broadest reasonable interpretation of these steps is that they may be accomplished by performing mental activities. For example, one may obtain data points and methylation indexes by reading information in a database or report. One may mentally comparing values to accomplish the comparing steps. One may mentally estimate the amount of cells in a sample by mentally comparing the methylation results to the calibration data. One may mentally identify methylation sites and differentially methylated regions after reading information in a database or report. One may also determine volumes and total methylation levels and individual methylation levels based on information read in a report or database. Thereby, each of the noted steps may be performed mentally and encompass an abstract idea.
Regarding the “inputting” step, one may accomplish this step by writing down methylation information or putting this information into a generic computer. However, the use of a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
Further, regarding claim 18, as stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Herein, the use of pen and paper or a generic computer to input data into a generic “calibration function” does not constitute something more than an abstract idea.
Additionally, the claims are considered to recite the judicial exception of a mathematical concept in that they require performing mathematical calculations. In particular, each of the claims requires “estimating” the amount of cells of a particular cell lineage based on comparing methylation levels ; claim 12 requires determining a methylation level using a first number and the volume of a cell free mixture ; and claim 18 requires inputting a first methylation level into a calibration function.
See MPEP 2106.04(a)(2):
A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.
Examples include
“v. using an algorithm for determining the optimal number of visits by a business representative to a client, In re Maucorps, 609 F.2d 481, 482, 203 USPQ 812, 813 (CCPA 1979); and
vi. calculating the difference between local and average data values, In re Abele, 684 F.2d 902, 903, 214 USPQ 682, 683-84 (CCPA 1982).”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited non-patent-ineligible steps of obtaining a cell-free mixture of DNA, obtaining reagents (or generating reagents in claims 19 and 20) that preferentially hybridize to differentially methylated regions, performing an assay that comprises contacting DNA fragments in the cell-free mixture with the reagents that hybridize to differentially methylated regions and detecting methylation based on signals generated by the assay are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited non-patent-ineligible steps of obtaining a cell-free mixture of DNA that comprises plasma or serum, obtaining reagents (or generating reagents in claims 19 and 20) that preferentially hybridize to differentially methylated regions, performing an assay that comprises contacting DNA fragments in the cell-free mixture with the reagents that hybridize to differentially methylated regions and detecting methylation based on signals generated by the assay obtaining a cell-free mixture of DNA, including PCR and sequencing assays, and detecting methylation based on signals generated by the assay are recited at a high degree of generality and were well-known, routine and conventional in the prior art. This finding is supported by the teachings in the specification – see, e.g., para [0044-0045], [0073], and [0106]). See also Dor et al (WO 2015/159292; cited in the IDS) which states “Methods of determining the methylation status of a methylation site are known in the art and include the use of bisulfite” (p. 30). Regarding the amendment to recite that the cell-free sample is obtained by separating the cell-free fraction from the cellular fraction, Dor teaches that such methods were well-known in the prior art. For instance, Dor states “According to one embodiment, a sample of blood is obtained from a subject according to methods well known in the art. Plasma or serum may be isolated according to methods known in the art” (p. 29, lines 6-8). Dor also states “Methods of isolating cell-free DNA from body fluids are also known in the art. For example Qiaquick kit, manufactured by Qiagen may be used to extract cell-free DNA from plasma or serum” (p. 30, lines 5-8). Liggett (J. Neurol. Sci. 2010. 290(1-2), p. 1-17; cited in the IDS) teaches methods of analyzing a sample to determine methylation levels wherein the methods comprising obtaining a blood sample from a subject, isolating plasma from the blood sample, isolating cell-free DNA from the plasma sample and contacting the cell-free DNA with reagents for performing PCR to detect the methylation level of CpGs in the cell-free DNA (e.g., p. 3). Similarly Gromminger et al (U.S. 20150322511) teaches methods for detecting cells of a particular origin in a blood sample from a subject wherein the methods comprise obtaining a blood sample from the subject; isolating plasma from the sample; and assaying cell-free DNA from the plasma by contacting the cell-free DNA with reagents that detect differentially methylated regions and performing PCR or sequencing of the cell-free DNA (e.g., para [0030], [37-41], [0070], and [0077-0078]). Gromminger teaches determining the absolute amount of DNA in the cell-free DNA that originated from a particular tissue using a standard curve (para [0078]). The methods of Dor and Gromminger also include obtaining and generating reagents that are used in PCR to detect methylation levels in differentially methylated regions of the genome, including primers. Note that the claims do not require any particular primers or probes. Further, while the claims define the distance between CpG sites, the claims do not require that the primer hybridizes to the full region of 100 to 166 bp or even that a primer pair amplifies a region of 100 bp to 166 bp.
Applicant’s attention is further directed to MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while claim 6 identifies a particular region of the genome that is differentially methylated – i.e., the FECH gene, the identity of the differentially methylated region is part of the judicial exception and not something in addition to the judicial exception. The claims do not require the use of a particular reagent, such as a particular primer or probe consisting of or comprising a specific nucleotide sequence. Since it was routine and conventional in the prior art to contact the bisulfite treated DNA with reagents, including primers and probes, that hybridize to the target sequence, the limitations regarding the use of a reagent that hybridizes to the target region (i.e., the FECH gene) do not add something ‘significantly more’ to the recited judicial exceptions.
Additionally regarding claim 18, to any extent that this claim intends to require a generic computer to input the methylation data, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f)).
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.Response to Remarks:
The response argues:
“the claims are directed to patent-eligible subject matter because they recite a laboratory method that requires obtaining a specific product defined by functional properties, and then using that product in a process that transforms a biological sample. The claims expressly require "obtaining reagents that preferentially hybridize to one or more differentially-methylated regions," where those regions are identified according to specific defined criteria, including methylation density thresholds, CpG site counts, and spatial relationships among CpG sites within a specified distance range..”
These arguments have been fully considered but are not persuasive. The claims do not in fact require obtaining (claims 1-6 and 9-18) or generating (claims 19 and 20) specific reagents. Rather, the claims generally recite obtaining or generating “reagents that preferentially hybridize to one or more differentially-methylated regions,” each of the one or more differentially-methylated regions having CpG sites with a 80% methylation density in an erythroid cell lineage and less than 20% methylation density in other cell lineages or having CpG sites that are within 100 to 166 bp. These are attributes of the differentially methylated regions per se that are required for the judicial exception of the correlation between the differentially methylated region and cels of a particular erythroid lineage. That is, the claims recite obtaining or generating reagents for the target region (DMR), which target region (DMR) is part of the judicial exception and not something in addition to the judicial exception. The claims do not require any particular reagents, and specifically do not require any particular primers or probes. Further, while the claims define the distance between CpG sites, the claims do not require that the primer hybridizes to the full region of 100 to 166 bp or even that a primer pair amplifies a region of 100 bp to 166 bp. There is no structure disclosed for the generic reagent recited in claim 1 or the primers or probes in claim 20, such as a nucleotide sequence. Thus, the claims do not require a “specific product,” but rather general reagents, including primers or probes, that would conventionally be used in assays for the detection of differentially methylated regions.
The response argues that the reagents are used to transform a particular article and thereby integrate the judicial exception into a practical application.
However, the fact that the claims require performing physically transformative laboratory steps is not sufficient to render the claims patent-eligible wherein the claims recite a judicial exception and those laboratory steps , using generically recited reagents, were well-known, routine and conventional in the prior art. Again, methods of performing an assay by contacting DNA fragments in a cell-fee mixture with obtained or generated reagents that preferentially hybridize to a target DMR were well-known, routine and conventional in the prior art.
The response argues:
“The claims are directed to an improvement in a technology or technical field within the meaning of MPEP § 2106.05(a) because they recite a specific method that increases the precision and reliability of hematologic diagnostics using cell-free DNA from plasma or serum.“
This argument has been fully considered but is not persuasive. Regarding “improvements,” Applicant’s attention is directed to MPEP 2016.04(d)(I) which states:
“It should be noted that while this consideration is often referred to in an abbreviated manner as the "improvements consideration," the word "improvements" in the context of this consideration is limited to improvements to the functioning of a computer or any other technology/technical field, whether in Step 2A Prong Two or in Step 2B.”
Herein, there is no showing that the claimed method results in an improvement in the functioning of a computer or an improvement to a technology or technical field. Applicant has asserted only that the claimed method improves the detection of hematological diseases, which is an improvement in the judicial exception itself. Further, the claims do not recite any limitations that incorporate the improvement into a practical application, such as a step of detecting the hematological disease by detecting the differential methylation indicative of erythroid cells in the plasma or serum sample and then administering a particular agent to treat the hematological disease in the subject diagnosed as having the hematological disease.
The response argues:
“MPEP § 2106.04(d)(I) instructs that claims integrate a judicial exception into a practical application when they recite additional limitations that impose meaningful limits on the scope of a judicial exception and do not merely monopolize the exception itself. The present claims satisfy this requirement by specifying an ordered combination of technical steps that are tied to a particular practical diagnostic application and that meaningfully limit any recited judicial exception.”
This argument has also been fully considered but is not persuasive. MPEP 2106.04 states:
While preemption is the concern underlying the judicial exceptions, it is not a standalone test for determining eligibility. Rapid Litig. Mgmt. v. CellzDirect, Inc., 827 F.3d 1042, 1052, 119 USPQ2d 1370, 1376 (Fed. Cir. 2016). Instead, questions of preemption are inherent in and resolved by the two-part framework from Alice Corp. and Mayo (the Alice/Mayo test referred to by the Office as Steps 2A and 2B). Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1150, 120 USPQ2d 1473, 1483 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1379, 115 USPQ2d 1152, 1158 (Fed. Cir. 2015). It is necessary to evaluate eligibility using the Alice/Mayo test, because while a preemptive claim may be ineligible, the absence of complete preemption does not demonstrate that a claim is eligible.
Herein, although the claims may include steps that involve laboratory procedures and may not monopolize the law of nature, as discussed in detail in the above rejection, the claims are not patent eligible using the Alice/Mayo test.
The rejection is maintained for the reasons set forth above.
New Claim Rejections - 35 USC § 112(b) - New Matter
5. 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 1-6 and 9-20 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 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. This is a new matter rejection..
The disclosure as originally filed does not provide basis for the amendment to the claims to recite “measuring an amount of cells of a particular erythroid cell lineage in a biological sample” (see claim 1).
This language includes methods that measure (and thereby distinguish between) different types of erythroid cells, such as erythroblasts, reticulocytes and red blood cells. See for instance claim 3 which recites “wherein the particular erythroid cell lineage is the red blood cell lineage.”
However, the originally filed disclosure provides basis only for the concept of measuring the number of cells of erythroid lineage.
In the reply of 03/06/2026, Applicant states:
“Claim 1 has been amended to recite that a cell lineage is "a particular erythroid cell lineage." Support can be found in, for example, paragraphs [0006] and [0052]-[0053] of the Application.”
However, paragraph [0006] recites “a particular hematological cell lineage (e.g., erythroblasts).” This provides basis for methods that measure the number of erythroblasts cells per se but does not provide basis for the distinct concept of detecting cells of a particular erythroid lineage, such that the method measures the number of reticulocyte cells without measuring the number or erythroblast cells to thereby measure a cell of a particular erythroid lineage, as is encompassed by the claims.
The cited teachings at para [0052-0053] disclose that “The contribution of the cell-free DNA from erythroblasts can be used to determine a level of a hematological disorder, such as anemia” (para [0052]). It is stated that “Accordingly, embodiments have identified erythroid DNA as a hitherto unrecognized major component of the circulating DNA pool and as a noninvasive biomarker for differential diagnosis and monitoring of anemia, as well as other hematological disorders” (para [0053]). Thus, the specification teaches detecting erythroid DNA, derived from erythroblasts, in circulating DNA.
The disclosure as originally filed does not teach that different erythroid cell lineages can be detected and distinguished from one another based on their methylation density at DMRs, as would be required to detect “cells of a particular erythroid cell lineage.” In fact, reticulocytes (immature non-nucleated red blood cells) and red blood cells (also non-nucleated) would generally not contain and release DNA into the blood stream. The teachings in the specification indicate that the circulating DNA detected in serum or plasma is derived from the erythroblast cells (e.g., para [0057-0058]). The specification (para [0059]) states “To validate our hypothesis and demonstrate the presence of erythroid DNA in plasma, we identified erythroblast-specific differentially methylated regions (DMRs) through analysis of the methylation profiles of erythroblasts and other tissue types.”
Accordingly, the originally filed disclosure provides support for methods for measuring an amount of cells of erythroid cell lineage, but does not provide support for the claimed methods of measuring an amount of cells “of a particular erythroid cell lineage.”
It is also noted that the response at page 7 states:
“claim 1 has been currently amended to recite cells from "a particular erythroid cell lineage," and a biological sample yielding a "cell-free mixture" that "comprises plasma or serum." As discussed during the Interview and acknowledged by the Examiner in the Interview Summary, the parent application, as filed, provides clear and sufficient support for these limitations.”
However, during the interview and in the interview summary, the examiner did not state that the disclosure provides support for the recitation of “measuring the amount of cells a particular erythroid cell lineage.” Rather, the interview summary states “Discussed amending the claims to recite that the method is one for measuring the amount of erythroid cells.” Measuring the amount of erythroid cells is distinct from the recitation in the present claims of measuring the amount “of a particular erythroid cell lineage,” as discussed above.
If Applicant maintains that the originally filed disclosure provides basis for the amended claims, Applicant should point to specific teachings (e.g., by paragraph number) in the present application to establish basis for each of the recitations set forth in the claims.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” which states:
“To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
Maintained / Modified Double Patenting
6. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 and 9-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11873527 (cited in the IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘527 are both inclusive of methods of measuring an amount of cells of a particular cell lineage in a biological sample comprising: obtaining a cell-free mixture of the biological sample, the cell-free mixture including cell-free DNA from a plurality of cell lineages; performing an assay by contacting DNA fragments in the cell-free mixture with reagents that preferentially hybridize to one or more differentially-methylated regions; detecting a first number of methylated or unmethylated DNA fragments in the cell-free mixture at the one or more differentially-methylated regions based on signals obtained from the assay; determining a first methylation level using the first number; obtaining one or more calibration data points, wherein each of the one or more calibration data points specifies (1) a calibration amount of cells of the particular cell lineage and (2) a calibration methylation level, and wherein the one or more calibration data points are determined from a plurality of calibration samples; comparing the first methylation level to a calibration methylation level of at least one of the one or more calibration data points; and estimating the amount of cells of the particular cell lineage in the biological sample based on the comparing. The claims of ‘527 meet the limitations of one of (c)-(f) of present claim 1 in that the claims of ‘527 encompass methods in which each of the CpGs are hypomethylated or hypermethylated and are within 100bp of each other. See claim 10 of ‘527: “wherein a first region of the one or more differentially-methylated regions comprises a plurality of CpG sites that are within 100 bp of each other, and wherein the plurality of CpG sites are all hypomethylated or hypermethylated.”
Claim 3 of ‘527 recites that “the particular hematological cell lineage is red blood cells.” Therefore, claim 3 of ‘527 recites the limitation of amended claim 1 of measuring the amount of cells of the cell lineage of red blood cells.
Further, claim 4 of ‘527 recites the limitation of amended claim 1 that the cell-free DNA is present in a plasma or serum sample.
The claims of ‘527 recite each of the limitations of present dependent claims 2-6 and 9-18. In particular, regarding present claim 6, the claims of ‘527 also encompass methods wherein the DMRs are in the FECH gene (see claim 6 of ‘527). Regarding present claim 9, claim 10 of ‘527 recites that the CpGs of the DMR are within 100bp of each other and thereby encompasses methods in which the DMRs are less than 200bp. Regarding claims 14-17, claim 1 of ‘527 further comprises obtaining of the one or more calibration data points by a method comprising “for each calibration sample of a plurality of calibration samples: measuring the calibration amount of cells of the particular cell lineage in the calibration sample; detecting a respective number of methylated or unmethylated DNA fragments in the cell-free mixture at the one or more differentially-methylated regions based on signals obtained from the assay applied to the calibration sample; and determining a respective calibration methylation level using the respective number.” Claims 15-18 of ‘527 recite the same limitations of present claims 15-18.
Regarding present claims 19 and 20, the claims of ‘527 do not recite generating the reagents for performing the assay and particularly generating primers or probes for the assay (claim 20).
However, the claims of ‘527 do recite “performing an assay by contacting DNA fragments in the cell-free mixture with reagents hybridizing to one or more differentially-methylated regions” and claim 5 of ‘527 recites that the assay for detecting methylation is PCR or sequencing assay. Since it was conventional in the prior art to performing PCR and sequencing assays using primers, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘527 so as to have included a step of generating the reagent that preferably hybridized to the differentially methylated region, and particularly a primer that preferably hybridized to the differentially methylated region in order to have facilitated performing the step of “contacting DNA fragments in the cell-free mixture with reagents hybridizing to one or more differentially-methylated regions” as required by claim 1 of ‘527.Response to Remarks:
The response states: “Because the current application is pending and the allowable claim scope has yet to be determined, Applicant respectfully requests that the double patenting rejection be held in abeyance until such time as the presence of otherwise-allowable subject matter is indicated.”
Applicant’s response has been fully considered. It is noted that rejections are not held in abeyance. The rejection is maintained for the reasons set forth above.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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