DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-7, species (1) (the step of determining at least one measure includes a step of determining at least one correlation coefficient for allele-specific amplification data of the first locus correlated with allele-specific amplification data of the second locus from the same volumes, see claim 3), and species (3) (the step of determining at least one measure includes a step of determining a number of volumes that exhibit co-amplification of a particular allele sequence of the first locus and a particular allele sequence of the second locus, and wherein the step of selecting a haplotype is based on the number of volumes, see claim 5) in the reply filed on July 27, 2026 is acknowledged. The traversal is on the ground(s) that: (1) “[F]irst, the Office has not shown that the alleged inventions are separately classified. To the contrary, the Office has classified each of Groups I-III within the same CPC subgroup (C12Q 1/6858) and has identified each group using the identical descriptor (‘a method of haplotype analysis’). By the Office’s own classification, the inventions are not separately classified, and prong (A) of MPEP § 808.02 is not satisfied. Second, the Office has not shown that the alleged inventions have a separate status in the art. No prior art has been cited as evidence of any such separate status, nor has the Office offered any explanation as to how Groups I-III occupy distinct positions within the relevant technical field. Therefore, Prong (B) of MPEP § 808.02 is not satisfied. Third, the Office has not identified a different field of search between the groups. Each group is directed to a method of haplotype analysis involving partitioning of nucleic acid into discrete volumes, allele-specific amplification at first and second polymorphic loci, and selection of a haplotype based on the amplification results. The distinctions among the groups reside solely in how the haplotype-selection step is characterized in the claim language. Group I recites selection ‘based on the at least one measure of co-amplification,’ Group II recites selection ‘based on the step of correlating,’ and Group III recites selection ‘based at least in part on whether the amplification data indicates a negative or a positive correlation.’ These are variations in claim wording and do not require different fields of search. Under MPEP § 808.02(C), the Office must identify the different fields of search with sufficient specificity to permit meaningful review. The Office fails to meet this burden. Indeed, because all three groups reside within the same CPC subgroup (C12Q 1/6858) and are directed to the same general subject matter, any search reasonably calculated to identify prior art relevant to one group would necessarily encompass prior art relevant to the others. For at least these reasons, Applicant submits that no serious search or examination burden has been established. Therefore, the requirement for restriction between the inventions of Groups I-III is improper”; and (2) “[A]bare assertion that individual searches do not overlap is not the equivalent of a showing that different fields of search are required. Under MPEP § 808.02(C), the Office must identify the different fields of search with sufficient specificity to permit meaningful review. The Office has failed to meet this burden. Indeed, because all species reside within the same CPC subgroup (C12Q 1/6858) and are directed to the same general subject matter (haplotype analysis by allele- specific amplification in partitioned volumes), any search reasonably calculated to identify prior art relevant to one species would necessarily encompass prior art relevant to the others. For at least these reasons, Applicant submits that an election between Species (1) and (2) and an election between Species (3) and (4) is improper”.
The above arguments have been fully considered and have not been found persuasive toward the withdrawal of the restriction requirement nor persuasive toward the relaxation of same such that Groups I to III and species (1) to (4) will be examined together. First, the restriction requirement on Groups I to III is not based on the separate classification and cited prior arts as argued by applicant. Since the restriction requirement mailed on May 28, 2026 clearly stated that “[G]roups I and II are distinct and independent inventions which are directed to two methods which have different properties. As a result, different and distinct searches will have to be performed. For example, the search required for Group I such as selecting a haplotype of the first and second loci based on the at least one measure of co-amplification in claim 1 is not required for Group II while the search required for Group II such as selecting a haplotype of the target region for the first and second loci based on the step of correlating in claim 8 is not required for Group I. Groups I and III are distinct and independent inventions which are directed to two methods which have different properties. As a result, different and distinct searches will have to be performed. For example, the search required for Group I such as selecting a haplotype of the first and second loci based on the at least one measure of co- amplification in claim 1 is not required for Group III while the search required for Group III such as selecting a haplotype of the nucleic acid based at least in part on whether the amplification data indicates a negative or a positive correlation for amplification of the allele sequences in the same volumes in claim 20 is not required for Group I. Groups II and III are distinct and independent inventions which are directed to two methods which have different properties. As a result, different and distinct searches will have to be performed. For example, the search required for Group II such as selecting a haplotype of the target region for the first and second loci based on the step of correlating in claim 8 is not required for Group III while the search required for Group III such as selecting a haplotype of the nucleic acid based at least in part on whether the amplification data indicates a negative or a positive correlation for amplification of the allele sequences in the same volumes in claim 20 is not required for Group II” (see pages 2 and 3), there is a search burden to search Groups I to III together. Second, although applicant argues that “[G]roup I recites selection ‘based on the at least one measure of co-amplification,’ Group II recites selection ‘based on the step of correlating,’ and Group III recites selection ‘based at least in part on whether the amplification data indicates a negative or a positive correlation.’ These are variations in claim wording and do not require different fields of search”, applicant has no evidence to show that Groups I to III do not require different fields of search and there is no search burden to search Groups I to III together. Third, applicant has no evidence to show that searches for species (1) and (2) are overlap and searches for species (3) and (4) are overlap. Furthermore, although the restriction requirement mailed on May 28, 2026 clearly stated that “[S]hould applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them 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 species 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 species” (eg., see page 4), applicant has not submitted evidence or identified such evidence to show that species (2) is an obvious variant of species (1) and species (4) is an obvious variant of species (3). Therefore, the requirement is still deemed proper and is made FINAL. Claims 1-3, 5, and 7 will be examined.
Information Disclosure Statement
IDS filed on April 19, 2024 contains 42 pages and 398 patent and non-patent literatures. However, since applicant has not submitted foreign patents from the patent literatures and the non-patent literatures or has not indicated where these foreign patents and non-patent literatures can be located, these foreign patents and non-patent literatures have been placed in the application file, but the information referred to therein has not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: (1) “in the volumes” in amplifying step should be “in the plurality of discrete volumes”; and (2) “the same volumes” in determining step should be “the same volumes from the plurality of discrete volumes”.
Appropriate correction is required.
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 1-3, 5, and 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. Claim 1 recites determining at least one measure of co-amplification of allele sequences from both loci in the same volumes and selecting a haplotype of the first and second loci based on the at least one measure of co-amplification, claim 3 recites a step of determining at least one correlation coefficient for allele-specific amplification data of the first locus correlated with allele-specific amplification data of the second locus from the same volumes, and claim 5 recites determining a number of
volumes that exhibit co-amplification of a particular allele sequence of the first locus and a particular allele sequence of the second locus. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The determining and selecting steps recited in claim 1 can be done by reading a report detailing SNP amplification data produced during the amplification step and deducing and assigning a haplotype appropriate for the data by thinking about the obtained data. For example, see the Table in page 10484 of Drydale et al., (PNAS 97, 10483-10488, 2000) and/or Table 2 of Hoehe et al., (Human Molecular Genetics, 9, 2895-2908, 2000) wherein both references show Haplotype assignment tables used to facilitate the assignment of a particular haplotype to individual sample tested for SNP status at a plurality of loci (i.e. a first polymorphic locus and a second polymorphic locus in claim 1) and can be accomplished by a mental processes, the determining step in claim 3 can be done by one of the most frequently used statistical procedure in biomedicine (see page 10 of Udovičič et al., Biochemia Medica, 17, 17, 10-15, 2007 and page 3566 of De La Fuente et al., Bioinformatics, 20, 3565-3574, 2004), and the determining step in claim 5 can be done by a simple math calculation.
For the reasons discussed above, the “determining” step and/or “selecting” step in claims 1, 3, and 5 could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exception claim 1 recites additional elements or steps “partitioning an aqueous phase containing nucleic acid into a plurality of discrete volumes” and
“amplifying in the volumes at least one allele sequence from each of a first polymorphic locus and a second polymorphic locus that exhibit sequence variation in the nucleic acid”. These additional elements do not amount to significantly more because they simply append a well understood, routine, and conventional activity previously known in the art, specified at a high level of generality, to the judicial exceptions.
The prior art demonstrates the well understood, routine, conventional nature of the additional element because it teaches that the additional elements are well known in the art. For example, see Fan et al., (Nature Biotechnology 29, 51-57, 2011) wherein Fan et al., teach a haplotyping method which comprises separating/partitioning an aqueous phase into a plurality of discrete volumes , see at least the Results section which begins on page 52. Fan further teaches amplifying in the volumes at least one allele sequence from each of a first polymorphic locus and a second polymorphic locus that exhibit sequence variation in the nucleic acid.
Further it is noted 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.
• 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);
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);
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);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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).
For the reasons set forth above the claims are not directed to patent eligible subject matter.
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, 2, 5, and 7 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 is rejected as vague and indefinite in view of selecting step. Since the word “measure” means a number that describes the size or quantity of something, such as the length of a line segment, the degrees in an angle, or the area of a shape (see the definition of “Measure”), the specification shows that “[A] haplotype can refer to two or more alleles that are present together or linked on a single chromosome (e.g., on the same chromosome copy) and/or on the same piece of nucleic acid and/or genetic material” (see paragraph [0169]), and claim 1 does not indicate that at least one measure of co-amplification of allele sequences from both loci determines nucleotide sequences of allele sequences from a first polymorphic locus and a second polymorphic locus, if at least one measure of co-amplification of allele sequences from both loci only determines a length of allele sequences from a first polymorphic locus and a second polymorphic locus, it is unclear why a haplotype of the first and second polymorphic loci can be selected based on the at least one measure of co-amplification such as a length of allele sequences from a first polymorphic locus and a second polymorphic locus. Please clarify.
Claim 5 is rejected as vague and indefinite. Since the word “volume” means a measure
of regions in three-dimensional space (see page 1 of “Volume” from Wikipedia), the number of volumes in claim 5 should be a number. Since the specification shows that “[A] haplotype can refer to two or more alleles that are present together or linked on a single chromosome (e.g., on the same chromosome copy) and/or on the same piece of nucleic acid and/or genetic material” (see paragraph [0169]), it is unclear why a haplotype of the first and second polymorphic loci can be selected based on the number of volumes. Please clarify.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
Claims 1 and 2 are rejected under pre-AIA 35 U.S.C. 102(e) as being anticipated by Quake et al., (US 2012/0196754, priority date: December 7, 2010).
Regarding claims 1 and 2, since the specification shows that “[A] haplotype can refer to two or more alleles that are present together or linked on a single chromosome (e.g., on the same chromosome copy) and/or on the same piece of nucleic acid and/or genetic material” (see paragraph [0169]), Quake et al., teach a method of haplotype analysis, the method comprising: partitioning an aqueous phase containing nucleic acid into a plurality of discrete volumes (ie., partitioning chromosome suspension into 48 compartments); amplifying in the volumes at least one allele sequence from each of a first polymorphic locus and a second polymorphic locus that exhibit sequence variation in the nucleic acid (eg., 46-loci PCR); determining at least one measure of co-amplification of allele sequences (ie., alleles X+Y) from both loci in the same volumes; and selecting a haplotype (ie., alleles X+Y) of the first and second loci based on the at least one measure of co-amplification as recited in claim 1 wherein the first and second loci are contained in a target region of the nucleic acid, and wherein the step of partitioning results in an average concentration of less than about five copies of the target region per volume (ie., each mixture containing one of homologous copy of each chromosome) as recited in claim 2
(see paragraphs [0045], [0047], [0072] to [0075], [00129], [00131] to [00133], [00135], and [00136], and Figures 2 and 4).
Therefore, Quake et al., teach all limitations recited in claims 1 and 2.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claim 3 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Quake et al., as applied to claims 1 and 2 above, and further in view of Udovičič et al., (Biochemia Medica, 17, 10-15, 2007) and De La Fuenta et al., (Bioinformatics, 20, 3565-3574, 2004)
The teachings of Quake et al., have been summarized previously, supra.
Quake et al., do not disclose the step of partitioning includes determining at least one correlation coefficient for allele-specific amplification data of the first locus correlated with allele-specific amplification data of the second locus from the same volumes from the plurality of discrete volumes as recited in claim 3.
Udovičič et al., teach that “[C]orrelation is a statistical procedure to calculate association between two variables. The value of the correlation is numerically shown by a coefficient of correlation, most often by Pearson’s or Spearman’s coefficient, while the significance of this coefficient is expressed by a p-value”, “[T]he statistical procedure of calculation is one of the most frequently used procedures in biomedicine. Correlation is agreement of values from two data sets, and it expresses the degree of association between investigated phenomena”, and “[D]etermination of association, ie., correlation between phenomena (variables) is an important tool in scientific study” (see abstract and pages 10 and 15).
De La Fuenta et al., teach discovery of meaningful associations in genomic data using partial correlation coefficients (see the title).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the method recited in claim 3 by determining at least one correlation coefficient for allele-specific amplification data of the first locus correlated with allele-specific amplification data of the second locus from the same volumes from the plurality of discrete volumes in view of the prior arts of Quake et al., Udovičič et al., and De La Fuenta et al.. One having ordinary skill in the art would have been motivated to do so because Udovičič et al., teach that “[C]orrelation is a statistical procedure to calculate association between two variables. The value of the correlation is numerically shown by a coefficient of correlation, most often by Pearson’s or Spearman’s coefficient, while the significance of this coefficient is expressed by a p-value”, “[T]he statistical procedure of calculation is one of the most frequently used procedures in biomedicine. Correlation is agreement of values from two data sets, and it expresses the degree of association between investigated phenomena”, and “[D]etermination of association, ie., correlation between phenomena (variables) is an important tool in scientific study” (see abstract and pages 10 and 15) while De La Fuenta et al., teach discovery of meaningful associations in genomic data using partial correlation coefficients (see the title). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to perform the method recited in claim 3 by determining at least one correlation coefficient for allele-specific amplification data of the first locus correlated with allele-specific amplification data of the second locus from the same volumes from the plurality of discrete volumes in view of the prior arts of Quake et al., Udovičič et al., and De La Fuenta et al., in order to calculate association between allele-specific amplification data of the first locus and allele-specific amplification data of the second locus from the same volumes from the plurality of discrete volumes.
Claim 7 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Quake et al., as applied to claims 1 and 2 above, and further in view of Roth et al., (US 2009/0098555 A1, published on April 16, 2009).
The teachings of Quake et al., have been summarized previously, supra.
Quake et al., do not disclose that the step of partitioning includes a step of forming an emulsion in which the volumes are droplets as recited in claim 7.
Roth et al., teach that a yeast culture (an aqueous suspension of cells) is mixed with oil to form a water in oil emulsion which contains emulsion droplets (‘bubbles’) such that the vast majority of bubbles contain either no cell or one yeast cell (see paragraph [0058]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the method recited in claim 7 by forming an emulsion in which the volumes are droplets in view of the prior arts of Quake et al., and Roth et al.. One having ordinary skill in the art would have been motivated to do so because Quake et al., teach to partition a chromosome suspension (see paragraph [00129]) while Roth et al., teach that a yeast culture (an aqueous suspension of cells) is mixed with oil to form a water in oil emulsion which contains emulsion droplets (‘bubbles’) such that the vast majority of bubbles contain either no cell or one yeast cell (see paragraph [0058]). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to perform the method recited in claim 7 by forming an emulsion in which the volumes are droplets before or during partitioning the chromosome suspension taught by Quake et al., in view of the prior arts of Quake et al., and Roth et al., in order to only amplify nucleic acids from a single specific chromosome.
Double Patenting
Claims 1-3, 5, and 7 are directed to the same invention as that of claims 1-3 and 7 of commonly assigned US Patent No. 11,499,181 B2. The issue of priority under pre-AIA 35 U.S.C. 102(g) and possibly pre-AIA 35 U.S.C. 102(f) of this single invention must be resolved.
The U.S. Patent and Trademark Office normally will not institute an interference between applications or a patent and an application having common ownership (see MPEP Chapter 2300). Either the applicant must amend or cancel claims such that the reference and the instant application no longer contain claims directed to the same invention, or the assignee must state which entity is the prior inventor of the commonly claimed subject matter. A terminal disclaimer has no effect in this situation since the basis for refusing more than one patent is priority of invention under pre-AIA 35 U.S.C. 102(f) or (g) and not an extension of monopoly.
Failure to comply with this requirement will result in a holding of abandonment of this application.
Conclusion
No claim is allowed.
Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center. The faxing of such papers must conform with the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993)(See 37 CAR § 1.6(d)). The CM Fax Center number is (571)273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph.D., whose telephone number is (571)272-0746. The examiner can normally be reached on Monday-Friday from 9 A.M. to 5 P.M.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Dr. Anne Gussow, Ph.D., can be reached on (571)272-6047.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/FRANK W LU/Primary Examiner, Art Unit 1683 September 22, 2025
