DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-9) and the species of (A) 7p, IKZF3, RAC2, TET2, and TNIP1, (B) a NOTCH inhibitor, and (C) a BCL2 inhibitor, in the reply filed on 4/2/2026 is acknowledged.
Given applicant’s election of the particular combination of variants of 7p, IKZF3, RAC2, TET2, and TNIP1, the variant classes that are being examined to be consonant with said election are mutations and somatic copy number alterations, as no variant corresponding to a structural variant was elected. This is relevant to claim 11, in that the oligonucleotides suitable for characterizing the variant classes only correspond to 7p, IKZF3, RAC2, TET2, and TNIP1 variants (mutations and SCNAs). Claim 11 requires that the oligonucleotides are for characterizing all of the variant classes. Therefore, claim 11 is withdrawn as being directed to a non-elected species. This is additionally relevant to claims 12 and 13. The elected species are directed to classes of variants corresponding to mutations and SCNAs and not structural variants. Therefore, claim 12 is being examined in so far as it requires measuring tumor mutational burden and claim 13 is being withdrawn as being directed to a non-elected species (microsatellite instability, a form of structural variant). It is also noted that the SEQ ID NOs of claim 13 do not all correspond to measurement of microsatellite instability (for example: SEQ ID NO: 6924 is for detection of a the TNIP1 gene).
Claims 1-22 are pending.
Claims 11 and 13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/2/2026.
Claims 1-10, 12, and 14-22 are being examined on the merits.
Upon further examination, the species election regarding a particular combination of variants to be characterized (selected from the list in claim 1) is partially withdrawn to include the variants of 17p (an SCNA according to Table 3) and NOTCH2 (a mutation according to Table 3). Consonant with the original election, only variants of the classes of SCNAs and mutations are examined. This partial withdrawal and rejoinder does not affect the requirement (as set forth on pages 4-5 of the papers of 02/02/2026) as it was applied to the other species that are the different genomic loci recited in the claims. With regard to the different species of variants encompassed by the claims, the species that are currently under examination are the combination elected by the Applicants (i.e.: 7p, IKZF3, RAC2, TET2, and TNIP1) and the species rejoined by the Examiner (i.e: 17p and NOTCH2).
Requirement for Information under 37 CFR 1.105
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application. The examiner found that an Oral Talk was given at the 61st ASH Annual Meeting on December 7-10, 2019 with the abstract of said talk naming several inventors on the instant application (Bjoern Chapuy, Timothy Wood, Andrew Dunford, Kirsty Wienand, Gad Getz, and Margaret Shipp). The title of the Oral Abstract is “Validation of the Genetically-Defined DLBCL Subtypes and Generation of a Parsimonious Probabilistic Classifier” (see attached oral abstract, Chapuy et al., 2019). The abstract indicates that there was a public disclosure of the 22 metafeatures as depicted in Table 3 (which are comprised of the variants of claim 1) for classification of DLBCL into 5 distinct subtypes through utilization of a molecular classifier. The Oral Abstract was published in Blood, Volume 134, Supplement 1, page 920 on November 13, 2019.
The examiner requires further information in order to make further determinations about the patentability of the instant claims. In response to this requirement, please provide the following answers and materials:
1. Were the variants of claim 1 publicly disclosed at the 61st ASH Annual Meeting?
2. Please provide a copy of the oral presentation titled “Validation of the Genetically-Defined DLBCL Subtypes and Generation of a Parsimonious Probabilistic Classifier”, and
3. Any additional presentation materials (such as a poster) that may have been presented at this conference.
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement. Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.58. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (see for example: pg 10, ln 25-30; pg 36, ln 15-25). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). The unlabeled sequences are on pages 13-14 of the instant specification.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: There is a reference to color in the figures (pg 23, ln 7, “green”) to describe a feature of the figure. Given that figures will only be provided in black and white (unless a petition is filed to include color drawings) references to colors in the figure should be avoided where possible.
Appropriate correction is required.
The use of the terms “AMPure” (pg 203, ln 26), “Quant-It” (pg 203, ln 29), and “NovaSeq” (pg 204, ln 18, 22-24), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 3 is objected to because of the following informalities: Claim 3(e)(i) reads “if the DLBCL is assigned to class C1 or C5” and should read “if the DLBCL is assigned to subclass C1 or C5” to maintain consistent claim terminology. Appropriate correction is required.
Claim Rejections – Improper Markush Grouping
Claims 1-10, 12, and 14-22 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Here, each species is considered to be a different method requiring characterization of distinct variants at distinct genomic loci or combination thereof.
The recited alternative elements do not share a single structural similarity, as each method relies on the detection/characterization of a different polynucleotide sequence/variation (i.e., nucleotide content in distinct genomic loci that may affect/alter the expression/function of a distinct gene). Each genetic locus having any different polynucleotide content has a different chemical structure in that it consists of a different nucleotide sequence. And each variant has a different biological activity in that it has a different specificity of hybridization required for identification/detection, and may alter expression/function of a different protein having a different biological activity. Thus, the species do not share a single structural similarity or biological activity. The only structural similarity present is that genetic elements are present in nucleic acids. The fact that the variants comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of “comprising a nucleic acid” alone is not essential to the common activity of being correlated with DLBCL classification, as asserted by the specification. Accordingly, while the different genetic variants are asserted to have the property of alterations present in different asserted classes of DLBCL, they do not share a single structural similarity essential to this activity.
Here it is clear that the asserted common use does not flow from any broadly ascribed common structure (MPEP 2117(II)(B)). The common use of being related to DLBCL is particular to each different variation (i.e., mutation or structural variation or somatic copy number alteration), not based on some particular common structural feature shared among the different variant loci themselves.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112a – Scope of Enablement
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 1-10, 12, and 14-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for classifying a DLBCL in a human subject through analysis of all classes of variants, does not reasonably provide enablement for characterization of at least two variants (which could be from the same class of alteration or two of the three listed classes of alterations) in any type of animal. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Nature of the invention and breadth of the claims
The claims are directed, as consonant with the species election, to the characterization of variants in a biological sample from a subject selected from the group consisting of 17p, NOTCH2, or the combination of 7p, IKZF3, RAC2, TET2, and TNIP1. The particular alterations corresponding to these variants, as taught by the instant specification (Table 3) are mutations and SCNAs. The scope of the claim does not require that all three types of alterations are present for the classification of DLBCL subclass. Additionally, the scope of the claim is to the classification of DLBCL in any type of subject, which the specification defines as “an animal” (human or non-human; pg 21, ln 17-18). The scope of the claim also includes the determination of only two metafeatures to be used in the computational analysis.
Direction provided by the specification and working example
The working examples provided by the specification teach the classification of DLBCL subclass in human samples using genetic data containing information on mutations, SCNAs, and SVs (pages 188-192). The examples provided characterized all variants of claim 1 and put into a minimum of 21 input variables (Table 3). As indicated by the specification, “removal of features or classes of alterations deteriorated the performance of the model” and “a further reduction of features (i.e., metafeatures) reduced the performance of the molecular classifier” (pg 192, ln 7-10). The specification does not provide any examples of the accurate classification of DLBCL subclasses in any animals besides humans.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to targeted sequencing of genes for alterations such as mutations, SCNAs, and SVs is high, the unpredictability in associating any type of genotypic variation encompassed by “mutation, a structural variation (SV), and a somatic copy number alteration (SCNA)” with a specific phenotype in any type of animal, as required by the claims, is higher.
Where the claims encompass detection of any type of mutation in the variants 17p, NOTCH2, or the combination of 7p, IKZF3, RAC2, TET2, and TNIP1, Hegele (2002) teaches the general unpredictability in associating any genotype with a phenotype. Hegele teaches that often initial reports of an association are followed by reports of non-replication and refutation (pg 1058, col 2, ln 24-30). Even in cases where an association between a articular gene and a phenotype state is known to exist, researchers have found that when using polymorphism analysis it was difficult to associate SNPs with disease states or to even identify key genes as being associated with disease (Pennisi, 1998).
Where the claims encompass any subject animal, it is relevant to point out the unpredictability in extrapolating the particular data of the specification to phenotypes in different non-human animals. Proteins with similar sequences may have markedly different functionalities in different organisms. Juppner (1995) teaches that despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics (Abstract; pg 39S-40S).
Quantity of experimentation required
A large and prohibitive amount of experimentation would be required to make and use the claimed invention. Within the scope of the claimed invention, one would need to determine which mutations, SCNAs, and SVs of the listed variants are associated with/can be used to determine DLBCL subclasses in any type of animal. Additionally, one would need to determine how to build a functional classifier with two variants (the minimum required by the claim) that would accurately determine the subclass of DLBCL. Even if such experimentation were performed it is unpredictable whether or not any associations beyond those of the instant specification would be identified, especially in non-human animal species.
Conclusion
After consideration of the teaching of the specification and the specific working examples, considering the breadth of the claims, and the unpredictability in the art, it is the conclusion that an undue and unreasonable amount of experimentation would be required to make and use the invention that is instantly claimed.
Claim Rejections - 35 USC § 112b - Indefiniteness
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 1-10, 12, and 14-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “characterizing variants in a biological sample from the subject, wherein the variants are selected from the group consisting of”. It is unclear how many variants are required to be characterized for the purposes of classification into one of five subclasses of DLBCL. For the purposes of examination, the use of the plural “variants” implies that at least two variants are characterized and therefore at least two variants selected from the group consisting of the listed genes are required to be characterized. However, further clarification is required.
Claims 2-10, 12, and 14-21 depend from claim 1, inherit this deficiency, and are rejected on the same basis.
Claim 4 is directed to the method of claim 3 “wherein the agent comprises”. However, it is unclear which agent from claim 3 is being further limited. Claim 3 defines 4 different agents ((e)(i) lines 3 and 5 and (e)(ii) lines 3 and 9) which are administered to the patient depending on the subclass of DLBCL. Claim 4 does not specify which agent is selected from the group of compounds. Given this ambiguity, and for the purposes of examination, it is being interpreted that this further limitation of “the agent” is providing further agents to choose from in each of “the agents” listed in (e)(i) and (e)(ii). However, further clarification is required.
Claim 4 contains the trademark/trade name “Adriamycin”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an agent and, accordingly, the identification/description is indefinite.
Claim 7 recites the limitation "the computational method" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 7 depends, defines a “a computational analysis”. It is unclear if this is the same analysis as in claim 1 or a new term that encompasses more method steps. For the purposes of examination this is being interpreted as the same computational analysis as in claim 1, however further clarification is required. If the claim term is indeed the same as in claim 1, then amendment to claim 7 to read “the computational [[method]]analysis” would clarify this issue.
Claim 10 is direct to the method of claim 1 “wherein (a) characterizing comprises targeted sequencing using a targeted sequencing panel”. Claim 1 already defines “a targeted sequencing panel” in line 19. It is unclear if this is the same targeted sequencing panel or if two different targeted sequencing panels are being used (one which is comprised of oligonucleotides as in claim 10 and one which could just be a panel of genes that are specifically amplified). The same problem arises with the limitation in claim 10 that two or more classes of variants are characterized in “a biological sample”. It is unclear if this is the same biological sample as already defined in claim 1, line 3 or if again, there are two different biological samples that are being processed using two different targeted sequencing panels. For the purposes of examination these are being treated as the same targeted sequencing panel and the same biological sample, however further clarification is required.
Claim 12 depends from claim 10, inherits this deficiency, and is rejected on the same basis.
Claim 14 recites the limitations "the at least one sample of oligonucleotides" and “the oligonucleotides suitable for use in targeted sequencing of the variant classes” in lines 9-11. There is insufficient antecedent basis for these limitations in the claim.
Claim 14 contains the claim terms “a subject” and “at least one patient”. It is unclear if and/or how these two classifications are different. The processor receieves a GSM array associated with at least one patient and then later on “characterizes DLBCL burden on a subject associated with the at least one patient”. It is unclear how “a subject”, if different from the at least one patient, is “associated with” the patient or how this subject would inform the classification of the patient. For the purposes of examination, the at least one patient and the subject are being treated as the same entity, however further clarification is required.
Claim 14 contains the term “DLBCL burden”. It is unclear what this term means. The term is mentioned twice in the specification on page 5, but no definition is provided. Is it the tumor mutation burden of the DLBCL of the patient? Is it the characterized subclass of the DLBCL as is being done in claim 1, from which claim 14 depends? For the purposes of examination, “DLBCL burden” is being interpreted as a DLBCL subclass. This is consistent with the purpose of the method of claim 1 and is in line with “wherein the at least one cluster identification characterized DLBCL burden”, with the at least one cluster identification being the categorization of the DLBCL into a subclass/cluster. However, further clarification is required.
Claims 15-17 depend from claim 14, inherit these deficiencies, and are rejected on the same basis.
Claim 18 is directed to the method of claim 1 “comprising use of a system”. Claim 18 then goes on to further limit how such a system is configured, but does not provide any active method steps (nor are any provided in the claims that depend from claim 18). No use of the system is particular pointed out with clear and defined practical steps, as is required for a “methods” claim. Therefore, the scope of claim 18 and its dependents is indefinite, given that it is unclear which statutory category claims 18-21 belong to and how itself would be considered a further limitation of a method claim without any active practical steps. .
Claim 18 recites the limitations "the at least one sample of oligonucleotides" and “the oligonucleotides suitable for use in targeted sequencing of the variant classes” in lines 11 and 13. There is insufficient antecedent basis for these limitations in the claim.
Claim 18 contains the claim terms “a subject” and “at least one patient”. It is unclear if and/or how these two classifications are different. The processor configured to receive a GSM array associated with at least one patient and then later on “characterizes DLBCL burden on a subject associated with the at least one patient”. It is unclear how “a subject”, if different from the at least one patient, is “associated with” the patient or how this subject would inform the classification of the patient. For the purposes of examination, the at least one patient and the subject are being treated as the same entity, however further clarification is required.
Claim 18 contains the term “DLBCL burden”. It is unclear what this term means. The term is mentioned twice in the specification on page 5, but no definition is provided. Is it the tumor mutation burden of the DLBCL of the patient? Is it the characterized subclass of the DLBCL as is being done in claim 1, from which claim 18 depends? For the purposes of examination, “DLBCL burden” is being interpreted as a DLBCL subclass. This is consistent with the purpose of the method of claim 1 and is in line with “wherein the at least one cluster identification characterizes DLBCL burden”, with the at least one cluster identification being the categorization of the DLBCL into a subclass/cluster. However, further clarification is required.
Claims 19-21 depend from claim 18, inherit these deficiencies, and are rejected on the same basis.
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 1-10, 12, and 14-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (e.g.: a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) is/are directed to a judicial exception encompassing abstract ideas and natural phenomena. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception as set forth below. The judicial exception is not integrated into a practical application of the judicial exception.
The following inquiries are used to determine whether a claim is drawn to patent- eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes - the claims are directed to methods.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes — Where the claims are directed to “characterizing the DLBCL” or “assigning the DLBCL as belonging to one of DLBCL subclasses C1 to C5” based on the observation of variant data, the claims are directed to an abstract idea; it is the mental identification of a phenotype, or the correlation of data and information. Where the claims are directed to “assigning a classification-specific weighted value”, “condensing the variant classification-specific weighted values into two or more metafeatures”, and “using the metafeatures as input variable for a computational analysis” for assigning the DLBCL to a subclass, the claims are directed to a mathematical concept (i.e., an abstract idea).
Furthermore, the claims are directed to an asserted correlation between DLBCL subclass based on variant classification and the phenotype of the tumor; such a correlation is a natural phenomenon which is a genotype:phenotype relationship.
Step 2A, prong 2. Does the claim recite additional elements that integrate the judicial exception into a practical application? No - The judicial exception(s) to which the claims are directed are not integrated into a practical application because there are no required particular practical steps recited with specificity related to the DLBCL characterization, such as applying a particular DLBCL subclass treatment to the subject. Here it is noted that claim 3(e)(i) and 3(e)(ii) require the administration of a particular treatment if the DLBCL is assigned to C1 or C5 ((e)(i)) or to C3 or C4 ((e)(ii)). However, claim 3 also encompasses the assignment of a DLBCL into subclass C2 (“(e)(iii) if the DLBCL is assigned to DLBCL subclass C2”). In this case, claim 3 has the limitation of “selecting a treatment” for those DLBCLs that are assigned to subclass C2 and does not require administering said treatment. Therefore, claim 3 does not require the administration of a particular treatment.
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No - The claims recite only routine steps related to detecting a variant in a biological sample through the use of a targeted sequencing panel.
“Hybridization techniques are well known to those skilled in the art” pg 19, ln 27-28
“Design and use of such amplification and sequencing oligonucleotides, and/or copy number detection probes/oligonucleotides (e.g., baits), can be performed by one of ordinary skill in the art.” pg 28, ln 31-33
“Methods for preparing libraries of polynucleotides for sequencing are known to one of skill in the art.” pg 29, ln 11-12
Additionally, it is noted that the specification indicates that the practical steps of data collection are known and routinely practiced by those of skill in the art. For example, the specification provides that “methods for preparing libraries of polynucleotides for sequencing are known to one of skill in the art” (pg 29, ln 11-12), “Methods of sequencing oligonucleotides and nucleic acids are well known in the art” (pg 32, ln 10-11), and “Methods for design and manufacture of a targeted sequencing panel are known in the art” (pg 43, ln 26-27).
So even where a practical step of the claim may require collecting variant data using conventional methods that have been practiced in the art, in University of Utah Res. Foundation v. Ambry Genetics Corp. (Fed Cir, 2014), the Court addressed claims that recite known methodological steps for collecting data (specifically genetic information) to be used in the application of a judicial exception, and held that:
Having determined that the comparison steps of claims 7 and 8 are abstract ideas, we move to the second step of Alice and ask whether the particular mechanism for the comparisons added by claims 7 or 8 renders the claims patent-eligible. For this step, Alice dictates that we ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “transform the nature of the claim’ into a patent-eligible application.” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297). There must be a further inventive concept to take the claim into the realm of patent-eligibility. Id. at 2355. The second paragraph of claim 7 describes the way in which the sequences are compared: they are compared by 1) hybridizing a BRCA gene probe and 2) detecting the presence of a hybridization product. Similarly, claim 8 requires 1) amplification of the BRCA1 gene and 2) sequencing of the amplified nucleic acids. The non-patent-ineligible elements of claims 7 and 8 do not add “enough” to make the claims as a whole patent- eligible.
For these reasons the claims are rejected under 35 USC 101 as directed to subject matter that is not significantly more than a judicial exception.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-7, 10, 12, and 22 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chapuy (Chapuy et al., US 2019/0292602 A1; cited on IDS of 9/15/2023).
Claims 1 and 3: Chapuy teaches a method of characterizing/classifying a DLBCL in a subject by characterizing variants in a biological sample from the subject wherein the variants include 17p and NOTCH2 (claims 1 and 3; paragraph [0008]). Chapuy teaches characterizing the variants through targeted sequencing, and that the variant classes include a mutation and an SCNA (paragraph [0008-0009]). Chapuy teaches selecting a treatment based on the assignment of the sample to 1 of 5 discrete subclasses of DLBCL (claims 1 and 3; paragraph [0008, 0019, 0087]). Chapuy teaches assigning a classification-specific weight value to each class of variant characterized wherein the weighted value reflects the magnitude of the characterized alteration in each class of variant and then condensing these weight values into two or more metafeatures which are then used in a computational analysis to assign the DLBCL to one of the DLBCL subclasses (claims 1 and 3; paragraphs [0104-0107, 0264-0266]). Chapuy teaches administering a NOTCH inhibitor if the DLBCL is assigned to subclass C1 or C5 (claim 3; the ABC-DLBCL subclasses, paragraph [0008, 0050, 0087, 0288, 0292]).
Claim 2: Chapuy teaches that subclass C3 and C5 are high-risk (paragraph [0305]).
Claim 5: Chapuy teaches that less than 25 metafeatures are used as the input (paragraph [0013]).
Claim 6: Chapuy teaches determining, if there is a mutation, if the mutation is a silent mutation or a non-synonymous mutation (paragraph [0264]).
Claim 7: Chapuy teaches that the computational analysis is an artificial neural network classification (paragraph [0014, 0104-0107]).
Claim 10: Chapuy teaches using a targeted sequencing panel that comprises oligonucleotides suitable for characterizing two or more classes of the variants in a biological sample (paragraph [0016]).
Claim 12: Chapuy teaches measuring tumor mutational burden using their methodology (paragraph [0044, 0077, 0236-0237]).
Claim 22: Chapuy teaches that subclass C2 is defined by variant 17p (paragraph [0305] and Figures 4 and 6F).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 4, 14, 16-18, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Chapuy (Chapuy et al., US 2019/0292602 A1; cited on IDS of 9/15/2023).
Claim 4: The teachings of Chapuy as they apply to claim 3, from which claim 4 depends, are detailed above. Chapuy does not explicitly teach administering an agent comprising rituximab. However, Chapuy does teach that 85% of patients that were analyzed for creation of the DLBCL classifier were uniformly treated with rituximab-containing CHOP-like regimen. It would have been prima facie obvious to those of skill in the art that an agent for treatment would be rituximab. One would be motivated to use this treatment given the teaching by Chapuy that this is a “state-of-the-art therapy” for DLBCL patients (paragraph [0214]).
Claims 14 and 18: The teachings of Chapuy as they apply to claim 1, from which claims 14 and 18 depend, are detailed above. Chapuy teaches generating a gene sample matrix (GSM) associated with a patient which represents an array that characterizes the classes of variants (which were characterized using a targeted sequencing panel comprising oligonucleotides suitable for sequencing the variant classes; paragraph [0264]). Chapuy teaches generating at least one metafeatures based at least in part on weighted sum of the classes of the variants in the at least one GSM array and then using a DLBCL classification machine learning model to generate a cluster identification categorizing the patient based on the metafeature and at least one trained classification layer which characterizes the DLBCL subclass of the patient (paragraphs [0104-0107, 0264-0267, 0309]). Chapuy teaches that the classifier, after arriving at a classification, designates the DLBCL as one of 5 subclasses (paragraph [0311]). Chapuy does not explicitly teach that these steps are performed using a processor and a computing device with an interface. However, it is noted that the courts have held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art (In re Venner, 262 F.2d 91, 95, 120 USPQ 193, 194 (CCPA 1958)). See MPEP 2144.04 III. Thus, performing any step of the claimed method with a computer is obvious. Chapuy also notes that all data processing “was performed in the Broad Firehose computing environment” and that “codes for modules from firehose as well as visualization and post-processing scripts are available upon request”, thus implying that their methodology was performed using a computer to perform the taught steps and that there is an interactive interface through which to visualize results (paragraph [0270]).
Chapuy teaches performing these steps in a computing environment, which inherently means that this is a system that is used to perform the method of claim 1 and is configured to perform all of the positive steps of claim 14 (relevant to claim 18).
Claims 16 and 20: Chapuy teaches the trained classification layer comprises an artificial neural network having learned weight for each of a plurality of neural network nodes (paragraphs [0104-0107]).
Claims 17 and 21: Chapuy teaches using a dimensionality reduction model to create a two-dimensional representation of the at least one metafeature and then generating a two-dimensional visualization comprising at least one labelled data point representing the metafeature and cluster identification associated with it (paragraph [0266] and Figures 5 and 16).
Claims 15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Chapuy (Chapuy et al., US 2019/0292602 A1; cited on IDS of 9/15/2023) in view of Monti (Monti et al., US 2020/0270702 A1, EFD of 12/23/2016).
The teachings of Chapuy as it applies to claims 14 and 18, from which claims 15 and 19 depend, respectively, are detailed above. Relevant to the instantly rejected claims, Chapuy teaches a computer system configured to carry out the classification of DLBCL subtype. Chapuy does not explicitly teach that the classification request is an electronic request over a network that then leads to the rendering of the DLBCL classification interface.
However, use of a computer system provided over an electronic network to receive requests for classifying a DLBCL subtype is known in the art, as taught by Monti.
Monti teaches providing a computer configured to carry out classifying steps for DLBCL over an electronic network (through which the request would be received; paragraph [0191]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Chapuy to modify the computer processing system to be provided over an electronic network, as taught by Monti. This is a simple substitution of a computer readable medium storage method on a local computer for an electronic network in which a central computer provides a service over a network such as the internet (paragraph [0191]). One would have a reasonable expectation of success given that Monti teaches using an electronic network computer configuration to process requests to classify DLBCL subtypes.
Claims 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Chapuy (Chapuy et al., US 2019/0292602 A1; cited on IDS of 9/15/2023) in view of Arzuaga-Mendez (Arzuaga-Mendez et al., Critical Review in Oncology/Hematology 2019).
The teachings of Chapuy as they apply to claim 1, from which claims 8 and 9 depend, are detailed above. Relative to the instantly rejected claims, Chapuy teaches that biological samples from subjects to classify DLBCL subtypes through characterization of variants can include blood samples (paragraph [0018]).
Chapuy does not teach that the biological sample comprises cell free DNA, and that the variants are characterized in the cell free DNA.
However, use of cell-free DNA for the characterization of variants in DLBCL is known in the art, as taught by Arzuaga-Mendez.
Arzuaga-Mendez teaches that cell-free DNA can be used to characterize variants in DLBCL samples including gene rearrangements and somatic mutations (Abstract).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Chapuy to characterize variants in cell-free DNA, as taught by Arzuaga-Mendez. One would be motivated to use cell-free DNA given the assertion by Arzuaga-Mendez that cell-free DNA obtained from liquid biopsy is “a non-invasive diagnostic and prognostic tool” (Introduction, paragraph 3). One would have a reasonable expectation of success of using cfDNA given the teaching by Arzuaga-Mendez that cfDNA as a biomarker was only evaluated in papers that obtained cfDNA from blood-derived fluids (2. Methods).
Conclusion
No claims are allowed.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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