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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The IDS received on August 25, 2023 is proper and is being considered by the Examiner.
Drawings
The drawings received on August 25, 2023 are acceptable.
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 1-18, 20, and 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 is indefinite for the following reasons:
Claim 1 recites the phrase, “human chromosome 6; and cytosine at position 28725934 of human chromosome 8, all cytosine positions in human chromosomes according to the chromosome map and sequence entries of database USCS Genome Browser on Human February 2009, GRCh37/hg19 assembly of the University of California Santa Crus (UCSC)”. Claim 1 recites a Markush language employing the transitional phrase, “selected from the group consisting of”, followed by a list of CpGs in the recited chromosomal locations. The members of this list are separated by the usage of a semi-colon (“;”). However, the subject-phrase, after the recitation of chromosome 6, a semi-colon, followed by the conjunction “and”, further recites what appears to be at least two additional members (i.e., all cytosines positions in human chromosome and sequence entries of database UCSC Genome Browser), reciting another conjunction “and” between these two members.
Therefore, the claim is indefinite in what the actual Markush group of members are. For the purpose of prosecution, the claim has been construed to recite all of the members in a single Markush Group. If this is the correct interpretation, Applicants are advised to amend the claim to reflect this.
Claim 3 is indefinite because claim seeks to redefine the Markush group of its parent claim 1, that is to say, claim 3 recites members of a Markush which is not found in the parent claim 1.
Claims 4-8 and 14-18 are also indefinite for the same reasons.
If Applicants are desiring to perform additional methylation determination steps with the subject-Markush groups, then the claims should clearly recite that this is a separate step from claim 1(a). For the purpose of prosecution, this assumption has been made.
Claims 2-18, 20, and 21 are indefinite by way of their dependency on claim 1.
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 1-9, 11-18, 20, and 21 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 a method which is for predicting a subject’s response to CAR T-cell therapy directed against B-lymphocyte antigen CD19, does not reasonably provide enablement for the method of prediction for the response to CAR T-cell therapy directed against any antigen. 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 use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure would require undue experimentation are summarized in In Re Wands (858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988)). They include (A) the quantity of experimentation necessary, (B) the amount of direction or guidance presented, (C) the presence or absence of working examples, (D) the nature of the invention, (E) the state of the prior art, (F) the relative skill of those in the art, (G) the predictability or unpredictability of the art, and (H) the breadth of the claims.
D & H - The nature of the invention & Breadth of Claims:
The nature of the invention relates to the determination of a subject’s propensity to respond to an anti-CD therapy based on the CpG methylation status of a T-cell produced from the subject. The breadth of the claims cover the method which predicts a subject’s response to CAR T-cell therapy directed against any antigens, not limited to the ones which Applicants appeared to have discovered (i.e., CD19):
“Chimeric antigen receptor (CAR) T-cell therapy has proved to be effective in patients for whom few therapeutic options otherwise remained, such as those with relapsed/refractory (R/R) B-cell malignancies. The use of autologous, genetically modified T-cells targeting the CD19 antigen (CART19) in pediatric B-cell acute lymphoblastic leukemia (ALL) have yielded complete response rates in around 80% of cases overall, the percentage was lower in older patients, leading to frequent long-term remissions” (page 1)
“Despite the great hopes that the use of CART19 cells has raised, treatment failure is not uncommon … The discovery of predictive biomarkers of response and outcome to CART19 therapy would be highly significant for risk stratification, the selection of alternative approaches for resistant/non-responder patients, and for improving newly developed CAR T-cell approaches” (page 1)
“Inventors surprisingly found out that a particular epigenetic profile observed in pre-infused CAR T-cells (in particular directed against CD19 (CART19), and based on DNA methylation microarrays, was associated with complete clinical response (CR) and improved event-free survival (EFS) and overall survival (OS) in patients with B-cell malignancy who received the adoptive cell treatment.” (page 3)
B – Amount of direction or guidance presented:
The specification discloses varying groups of CpG sites found on the CAR T-cells (EPICART) derived from the subject being evaluated for his/her response to CAR T-cell therapy:
“determining the methylation status of one or more CpG sites of CAR T-cells, said CAR T-cells obtained from an isolated sample of the subject comprising T-cells that, once isolated, have been transduced with the CAR” (page 3)
“the one or more cytosines in CpG sites of CAR T-cells selected from the group consisting of cytosine at position 86332162 of human chromosome 2, cytosine at position 188676237 of human chromosome 1; cytosine at position 10907265 of human chromosome 6; cytosine at position 234087867 of human chromosome 1; cytosine at position 32353565 of human chromosome 11; cytosine at position 22634199 of human chromosome 10; cytosine at position 45028225 of human chromosome 2; cytosine at position 220414164 of human chromosome 1; cytosine at position 209809 of human chromosome 6; cytosine at position 62905816 of human chromosome 1; cytosine at position 79780164 of human chromosome 6; and cytosine at position 28725934 of human chromosome 8; all cytosine positions in human chromosomes according to the chromosome map and sequence entries of database USCS Genome Browser on Human February 2009; GRCh37/hg19 assembly of the University of California Santa Cruz (USCS)” (page 4)
“using these sites linked to CR, particular signature (termed in this description EPICART and EPICART18) were established, which were associated with CR and enhanced EFS and OS1” (page 5)
The specification discloses a list of 18 CpG sites which are correlated with CR (see page 16).
The specification further teaches and provides guidance in obtaining the CpG methylation status via means which are well-established in the art, such as the use of an array (see page 23, for example, also below):
“One of the most common includes the use of probes that are specific for the methylation sites. Thus, in another particular embodiment … methylation status of the one or more cytosines in the CpG sites is determined with a set of DNA oligonucleotides comprising one or more oligonucleotides that are complementary to a sequence comprising the cytosine of each CpG and producing a differential signal if the cytosine in determined position is methylated or unmethylated” (page 23)
“the methylation status of any individual cytosines or a group of cytosines in the genome of a CAR T-cell (e.g., CD8 T cell) can be determined using standardised methodologies, including among others the Infinium MethylationEPIC Array (approximately 850,000 CpG sites) and the automated processing of arrays with a liquid handler …” (page 24)
However, the specification only teaches the CpG sites and their methylation status that correlate with CAR T-cell therapy directed against a specific antigen, CD19. There are no data that relate the CpG sites and their methylation status to CAR T-cell therapy that are directed to other known types of antigens targeted in the art, such as CD22, BCMA, CD70, etc.
C –Presence/Absence of Working Examples:
As discussed above, the specification provides working examples of where the CpG sites of CAR T-cells against CD19 antigen and their correlation to the response of a subject receiving the CAR T-cell therapy. However, the specification does not provide any other correlation to CAR T-cell therapy targeting different known antigens.
F & G – Skill level of the artisan & Unpredictability of the art:
The skill level of the artisan is deemed high, but the correlation of markers to a particularly observed phenotype remains largely unpredictable, requiring a large size sample of study, and well-designed study to discover whether such correlation even exists.
A & Conclusion:
Therefore, for the reasons discussed above, the quantity of the experimentation necessary would be undue for collecting the statistically significant numbers of subject samples, identification of the CpG sites that from CAR T-cells that target other known antigens, and determining, if there even exist such a correlation, resulting in the one of skill in the art being incapable of practicing the claimed method fully commensurate in scope without undue experimentation.
Claims 1, 3, 5, 7, 9-14, 16, 18, 20, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description Rejection.
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
The written description requirement ensures that, “an applicant invented the subject matter which is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure) (MPEP 2163 at II(A)(3)(a)(ii)).
Reduction to Practice
The specification discloses a set of specific CpG sites from CAR T-cells produced from T cells that have been transduced with CAR, wherein the antigen to which the T-cell target is CD19.
The claims, however, recite that the CpG sites one of more of any cytosine positions in human chromosomes according to the chromosome map and sequence entries of database USCS Genome Browser.
The Office has determined that a handle of CpG sites discovered by Applicants are not representative of number of species in order to justify the correlation of any cytosines found in human chromosomes in a chromosome map as presently claimed, as well as CpGs of CAR T-cells that target antigens other than they were specifically discovered (i.e., CD19).
Reduction to Drawing
The specification only discloses the data pertaining to the specific CpG sites and their correlation for the response of a subject to CAR T-cell therapy that target CD19.
Disclosure of Relevant Identifying Characteristics
While one could argue that a skilled artisan would be able to identify the “representative number of species” of the cytosines in human chromosomes, such method would not satisfy the written description for the genus claims when, “the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art” (MPEP 2163(I)(A)). For the claims at issue, such essential or critical feature is the actual CpG sites which show the required correlation. Applicants have not disclosed enough number of species within the claimed genus to justify the presently claimed genus.
As stated in University of California v. Eli Lilly and Co. at page 1404:
An adequate written description of a DNA ... "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Therefore, for the foregoing reasons, the genus embraced by the claims is not sufficiently described by the number of species disclosed in the specification, and therefore, the specification lacks written description of the claims.
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 1-18 and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite the data determination and comparison of the determined data to a reference data/value. This judicial exception is not integrated into a practical application because mere collection of data and comparison of data to a referenced data/value are steps tantamount to data harvesting and manipulation with no practical application.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the analysis under the current Patent Eligibility Guidelines (herein, “PEG”) as discussed below.
Step 1 Inquiry under PEG
Step 1 inquiry under Patent Eligibility Guidelines (herein, “PEG”) determines whether or not the claimed invention is drawn to one of the recognized statutory classes of invention. Claims 1-18, and 20 satisfy the present inquiry as being drawn to a method.
Step 2A Inquiry under PEG
A recently revised PEG now performs step 2A inquiry under a 2-prong analysis, and the subject claims analyzed accordingly as follows:
Prong 1:
Prong-1 inquiry under step 2A determines whether the claims recite an abstract idea, a law of nature, or a natural phenomenon. As stated above, independent claim 1 recites the judicial exception of determining the methylation status of CpG sites and comparing the determined status with a reference CpG methylation status. While the claim recites that the status of CpG sites is obtained from a sample, the claimed method does not require that the method of obtaining the CpG sites are performed. These steps are deemed data harvesting and manipulation, which are deemed to be judicial exception. As well, claim 1 also embraces performing the steps in the mind (i.e., mental steps), a judicial exception. Independent claim 20 further recites a step of “deciding and/or recommending” to initiate an autologous CAR T-cell therapy based on the determination. However, this step embraces a “do nothing” approach, therefore, does not meaningfully apply the Therefore, claim recites a judicial exception. The dependent claims 2-8 and 14-18 depend from claim 1, and recite a different groups of CpG sites from which the data are harvested and manipulated but as stated above, these are data harvesting and manipulation which are judicial exceptions.
Prong 2:
Prong-2 inquiry under step 2A determines whether or not the claims recite additional elements that integrate the judicial exception into a practical application in a manner that imposes a meaningful limit on the judicial exception.
The dependent claim 9, recites that sample from which the data is harvested is selected from a biofluid including lymphocyte T cells. However, the claimed method does not actively perform this step, but simply recite the source of the data and therefore does not actively limit the judicial exception discussed above.
The dependent claim 10 recites that the CAR (chimeric antigen receptor) T-cells target CD19. However, the claim simply further defines the source of the data and therefore do not add significantly more to the judicial exception (i.e., data) itself.
The dependent claim 11 recites the manner in which the data is harvested, via means of oligonucleotides, but as stated above, these steps are not construed to be actively performed as part of the steps, but simply recite the manner in which the data was harvested. Therefore, the claim does not add significantly more to the judicial exception.
The dependent claims 12 and 13 recite that the response is a complete response and that the subject is suffering from B-cell malignancies, but this also is what the data represent and therefore do not add significantly more to the judicial exception.
As explained by the Supreme Court, in order to transform a judicial exception into a patent-eligible application, the additional element or combination of elements must do ‘more than simply stat[e] the [judicial exception] while adding the words ‘apply it’”. Alice Corp. v. CLS Bank, 573 U.S. __, 134 S. Ct. 2347, 2357, 110 USPQ2d 1976, 1982-83 (2014) (quoting Mayo Collaborative Servs. V. Prometheus Labs., Inc., 566 U.S. 66, 72, 101 USPQ2d 1961, 1965). Thus, for example, claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 134 S. Ct. at 2358, 110 USPQ2d at 1983. See also 134 S. Ct. at 2389, 110 USPQ2d at 1984 (warning against a § 101 analysis that turns on “the draftsman’s art”) (MPEP 2106.05(f))
Step 2B Inquiry under PEG
Step 2B inquiry of the PEG determines whether or not additional elements are provided and whether such elements amount to significantly more than the judicial exception in the claims.
As discussed above, the additional elements which are provided in the above-discussed claims 9-13 fail to further add more than the judicial exception because the claims simply define the data itself and there are no active steps required of the claims other than harvesting and manipulating the collected data, and therefore do not specifically limit recited judicial exception.
Therefore, these elements are not deemed significantly more than inclusion of that are commonly used, routine and conventional.
Therefore, the present claims lack patent eligibility.
Conclusion
No claims are allowed.
Claim 21 satisfies the patent eligibility under 35 U.S.C. 101 because the claim actively recites the step of isolating an identified candidate CAR T-cells or a population thereof based on the method that identifies CAR T-cells which provides a benefit to a subject of interest based on the harvested and manipulated data, thereby actively applying the judicial exception into a practical application.
The Office also notes that the methylation status of the CpGs in the CAR T-cells and the correlation to a subject’s response to CAR T-cell therapy is not a naturally occurring phenomenon. This is because the CpG status is not determined from a naturally existing in the T-cell of the subject, but the T cells which have been infused with CAR2. Therefore, the CpG status of CAR T-cells are not from a naturally existing product (i.e., not a judicial exception).
The prior art does not teach or suggest for a method of predicting a subject’s response to autologous CAR T-cell therapy based on the methylation status of the recited CpGs in CAR T-cells. While the prior art teaches looking at gene expression profiles of the CAR T-cells between varying responders and non-responders (Fraietta et al., Nature Medicine, 2018, pages 1-16; IDS ref), or looking at certain gene disruptions that regulate methylation (Fraietta et al., Nature, 2018, pages 1-27; IDS ref) which result in an improvement of CAR T-cell therapy, none of the teachings teach the presently recited CpG sites and their methylation status to a subject’s propensity to respond to CAR T-cell therapy.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 December 30, 2025
/YJK/
1 The terms, “CR,” “EFS,” and “OS” are defined on page 5 as, “Complete Response,” Event-Free Survival,” and “Overall Survival”.
2 “CAR” is Chimeric Antigen Receptors that is engineered fusing heavy and light chain variable regions of a monoclonal antibody directed against an antibody to TCRs (T-cell receptors), see Majzner et al. (Cancer Discovery, October 2018, pages 1-9).