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, species a mutation in EZH2 in the reply filed on 7/20/2026 is acknowledged.
Claim 9 is WITHDRAWN because it does not recite detection of the elected EZH2 mutation.
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 1-8 and 10-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, consonant with the election requires detecting “a mutation” in EZH2. This is understood to mean that the presence of a mutation in EZH2 must be detected. The claim does not require that the presence of the mutation is detected in the nucleic acid sample. The scope of the “detecting” in claim 1 as it is written encompasses detecting a mutation in EZH2 DNA, RNA or even protein. The claim recites detecting “a mutation” or “at least one genomic alteration,” with “a mutation” being elected.
The, claim 2 requires that “the DNA” comprises cell free DNA, but the claim does not require that a mutation or genomic alteration is detected in the cell free DNA or in DNA at all.
Claim 3 further requires isolating the DNA from circulating PBMC in the biological sample. However, the claim does not previously require that “the biological sample” have PBMC, so “the DNA from circulating PBMC” lacks proper antecedent basis in this context and claim 3 is indefinite for this reason. Claim 3 does not require detecting anything in the DNA isolated from PBMC.
Therefore, claim 4 is indefinite when it refers to “the mutations” in the cfDNA and the DNA from the circulating PMBC because the claim (1) never previously requires “mutations” plural (2) never previously requires detecting a mutation in either cfDNA or the DNA from circulating PBMC and (3) the claim encompasses detecting “at least one genomic alteration” instead of a mutation and it is not clear if claim 4 is meant to limit the claim to require detecting “a mutation.”
When claim 7 recites “wherein the mutation is detected in” it is not clear if this is simply meant to limit the choices of genes claim 1(i) is practiced or if it is meant to require that the option for detecting “a mutation” is required in claim 7. This is relevant since detecting “a mutation” is only an option in claim 1, not required.
Claim 10 recites that it is a method of “distinguishing” RS from CLL but there is no method step directed to the distinguishing and so it is not clear if the method is meant to require distinguishing or if practicing the steps of the method are sufficient to accomplish the intended use. Furthermore, the final “wherein” clause does not set forth “distinguishing” the two phenotypes, but instead sets forth a possibility that RS will or will not develop which does not distinguish RS from CLL. The final “wherein” clause is not a step, it is a statement of inherent properties of the meaning of the mutation.
Claim 10, consonant with the election requires detecting the presence or absence of “a mutation” in EZH2. The claim does not set forth that the mutation is detected “in the biological sample.” The scope of the “detecting” in claim 10 as it is written encompasses detecting a mutation in EZH2 DNA, RNA or protein. The claim recites detecting presence or absence of “a mutation” which is singular.
Claim 11 requires that “the biological sample” comprises cell free DNA, but the claim does not require that a presence or absence is detected in the cell free DNA or in DNA at all.
Claim 12 further requires isolating the DNA from circulating PBMC in the biological sample. However, the claim does not previously require that “the biological sample” have PBMC, so “the DNA from circulating PBMC” lacks proper antecedent basis in this context and claim 12 is indefinite for this reason. Claim 12 does not require detecting anything in the DNA isolated from PBMC.
Therefore, claim 13 is indefinite when it refers to “the mutations” in the cfDNA and the DNA from the circulating PMBC because the claim (1) never previously requires “mutations” plural and (2) the claim never previously requires detecting a mutation in either cfDNA or the DNA from circulating PBMC.
Claim 14 is indefinite because it recites “determining the RS subtype” but the it is unclear what “the RS” refers to because the patient has not been required to have or be diagnosed with RS previously in the claim. Further, it is not clear what is required to “determine the RS subtype” further than detecting the previously required presence or absence of at least one mutation. Further, in the “determining” step, the recitation of “the detection of” of the at least one genomic alteration lacks proper antecedent basis because the claim does not previously require detecting a genomic alteration, it clearly encompasses detecting the “absence” of a genomic alteration. It is unclear what is required of the determining step in the embodiment where the “absence” of the genomic alteration is detected.
In claim 16 requires “comparing the mutations in the cfDNA and the DNA from circulating PBMCs” but this phrase lacks proper antecedent basis because claim 16 does not previously set forth “mutations” that were detected in PBMC or cfDNA at all.
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 4 and 10-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea and/or law of nature without significantly more.
Claim 4 recites a mental process of “comparing the mutations” which is a mental process abstract idea. This judicial exception is not integrated into a practical application because the claims do not apply or use the judicial exception in any way. The steps in addition to the judicial exception are data gathering steps. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exception are data gathering steps recited at an extremely high level of generality instructing the skilled practitioner to detect the mutation using any known method. Methods wherein cell free DNA and DNA from circulating cells were both isolated and nucleic acid content was detected were known before the invention. See for example, Brannon et al. and Rosa et al.
Claims 10-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea and law of nature without significantly more. The claim(s) recite(s) “distinguishing Richter’s Syndrome (RS) from chronic lymphocytic leukemia (CLL)” which is a mental process judicial exception. Furthermore, the claims set forth that the subject will develop RS if a mutation or alteration is detected and will not develop RS if a mutation is not detected. This sets forth the naturally occurring relationship between particular genomic content and the detecting, which is a natural phenomenon. Claims 13 and 14 further recite “comparing the mutations” which is an abstract idea judicial exception. Claim 14 further sets forth “determining the RS subtype based on the detection of the at least one genomic alteration” and this is a mental process idea. Furthermore, the “wherein” clauses in claim 14 sets forth naturally occurring relationships between particular genomic subtypes and genomic content, which are naturally phenomenon.
These judicial exceptions are not integrated into a practical application because the claims do not apply or use the judicial exceptions in any way. The steps in addition to the judicial exceptions are extra-solution data gathering steps. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exceptions are extra solution data gathering steps which direct the skilled practitioner to gather data using any possible known technique. Methods for obtaining biological samples and isolating cell free and cellular DNA from them were conventional before the effective filing date. See for example, Brannon et al. and Rosa et al.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 2, 6, 7, 8, 10, 11, and 14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (PLoS ONE 11(12):e0167641; 24 pages plus supplemental materials).
Kim et al. teach obtaining a biological sample from a subject that has been diagnosed with chronic lymphocytic leukemia. The reference teaches isolating a nucleic acid sample comprising DNA or RNA from the biological sample and detecting a mutation in EZH2. See p. 3, Targeted Sequencing. See Table 1 Which teaches two different mutations detected in two different CLL patients. See also p. 5, Validation with Sanger Sequencing.
Regarding claim 2, bone marrow comprises cell free DNA, inherently.
Regarding claim 6, the reference teaches detecting the mutation with sequencing. See p. 3 and p. 5.
Regarding claim 8, the reference further teaches detecting a mutation in SF3B1, see Table 1. Note here, that the claim does not require where the mutation is detected, that is, it does not require that the mutation is detected in the same biological sample, for example.
Regarding claim 10, the reference clearly teaches the obtaining and detecting steps, wherein a mutation is detected in EZH2. The final “wherein” clause sets forth inherent properties of the presence or absence of a mutation but does not require any step or action that distinguishes the claimed method from the method taught in the reference.
Regarding claim 11, bone marrow comprises cell-free DNA, inherently.
Regarding claim 14, the reference teaches detecting SF3B1 mutation, see Table 1. Regarding the “determining” step, it is not clear that determining the subset requires anything further than detecting the SF3B1 mutation, which “indicates” RS subtype 4.
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.
Claim(s) 2, 3, 4, 5, 11, 12, 13, 15 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. in view of Brannon et al. (Nature Communications(2021) 12:3770; 12 pages).
The teachings of Kim are given previously in this Office action and are fully incorporated into this rejection.
Kim does not teach isolating the DNA from blood or circulating peripherial mononuclear cells and comparing a mutation in the cfDNA to DNA from circulating PMBCs.
Brannon teaches that detecting cancer mutations in cfDNA has provided a means to overcome the limitations of tissue profiling and can have a direct impact on patient care (p. 2, Col. 1). The reference teaches a clinical test that can detect somatic genetic alterations in cfDNA specimens (p. 2, Col. 1). The workflow includes isolating DNA from plasma (cfDNA) well as from the white blood cells, which are PMBC. See Figure 1b and related description and p. 9, 2nd column. The reference teaches sequencing both types of DNA and comparing the mutations present therein.
It would have been obvious to have modified the method taught by Kim et al. so as to have also sequenced DNA from blood cells and cell free portions of the DNA in order to develop a method for detecting the identified cancer mutations in a less invasive sample, namely from blood, as taught by Brannon.
Claim Rejections - 35 USC § 112
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 1-8 and 10-16 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.
The claims are drawn to detecting any possible mutation of EZH2 a biological sample obtained from a patient who has or is suspected of having chronic lymphocytic leukemia (CLL) or has been diagnosed with or is suspected of having Richter’s Syndrome (RS).
The genus of detected mutations includes all possible mutations in the gene; the fact that they must be in a biological sample means they must be naturally occurring.
The specification does not provide a particular definition for “mutation” but this word is understood according to its common meaning in the prior art. For example, National Cancer Institute defines mutation as follows:
“Any change in the DNA sequence of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Mutations can be harmful, beneficial, or have no effect. If they occur in cells that make eggs or sperm, they can be inherited; if mutations occur in other types of cells, they are not inherited. Certain mutations may lead to cancer or other diseases. A mutation is sometimes called a variant.”
Claims 1 and those that depend on it merely require detecting mutations; while claims 10 and those that depend on it further require that the detected mutations are indicative of the phenotypes set forth.
The specification describes only two mutations identified in biological samples from individuals with Richter’s syndrome: namely a nonsense mutation identified in patient 25 at position 540 and mutation Y641H/S identified in Figure 6H.
The prior art of Kim teaches a non-synonymous change at A646V in one patient and a p.388_397del in another patient. Both of these patients had CLL. See Kim Table 1.
Thus there is very little known in the prior art about mutations present in EZH2 in patients with CLL.
The genus of possible mutations encompassed for detection in the claims is immense, while the written description of detected mutations in biological samples as drivers of Richter’s syndrome is extremely limited.
The specification describes the complete structure of only two species in the claimed genus.
The specification does not describe other species in the genus by structure, or physical and/or chemical characteristics. The functions of the other species in the genus are not disclosed, and there is no known or disclosed correlation between the unknown structures and the being present in the required biological samples, or indicative of the presence, absence or potential to develop RS, or between the unknown structures and the structure of the single species disclosed.
The specification does not provide any guidance as to how to identify other mutations that occur in subjects with CLL or RD, or suspected of them. There is no description of the mutational sites that exist in nature, and there is no description of how the structure of the known EZH2 gene or disclosed mutations relates to the structure of different naturally occurring mutations. The general knowledge in the art concerning mutations does not provide any indication of how the structure of one mutation is representative of other unknown mutations having concordant or discordant functions. The common attributes of the genus are not described and the identifying attributes of individual mutations, other than the limited genus disclosed, are not described. The nature of mutations is that they are variant structures where the structure and function of one does not provide guidance to the structure and function of others. In other words, the existence of other mutation is unpredictable and the structure of other mutations, if they exist, is also unpredictable. In addition, according to the standard definition, the genus might include members that have widely divergent functional properties, as evidenced by the fact that one mutation disclosed is a loss of function mutation and one is gain of function mutation and both are disclosed within the claimed genus. One of skill in the art would conclude that the applicant was not in possession of the claimed genus because a description of only one member of this genus is not representative of the variants of the genus and is insufficient to support the claim.
Improper Markush Rejection
Claims 1-8 and 10-16 are rejected on the basis that it contains 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 all different target genes and also all different genomic alterations 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:
The target genes and genomic regions do not all share a common structure; they are represented at different positions in the genome.
They also do not all function the same; some drive clonally related RS and some drive clonally unrelate RS, some are activating of the target gene or region some deactivating, some indicate good prognosis some indicate poor prognosis. They indicate different “types” of RS. They are not interchangeable in the claimed methods.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/ Primary Examiner, Art Unit 1682
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