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 and species (a), that is, NRP2-ALK fusion, in the reply filed on June 22, 2026 is acknowledged.
The Office acknowledges the cancelation of claims directed to non-elected invention, that is, Group II (i.e., claims 110, 111, 113, 116, 123, and 154).
Claims 74, 79, 84, 89, 94, 99, and 104 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (i.e., non-elected species), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 22, 2026.
Information Disclosure Statement
The IDS received on July 16, 2024 and June 22, 2026 are proper and are being considered by the Examiner.
Drawings
The drawings received on March 6, 2024 are acceptable.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see section [0216], for example referring to clinicaltrials.gov). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code that are disclosed in the specification; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 63, 64, 67, 70, 170, 177, and 197 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 63 is indefinite because the steps of detection and the treatment are disjointed and fails to provide a nexus as discussed below.
Claim 63 is directed to a method that treats or delays the progression of cancer. The claim recites the steps of detecting a large genus gene fusion sequences (or its encoded protein product), from a subject already known to have cancer (i.e., “detecting in a sample from an individual having cancer”), followed by the administration of an effective amount of an anti-cancer therapy.
Because the subject is already known to have cancer, the application of an anti-cancer therapy is a routine process. However, the claim recites the detection of the various gene fusion sequences, without reciting how their detection is relevant to the administration of the anti-cancer therapy, failing to recite a nexus between the detection and the therapy. If the detection of these fusion sequences provides no additional bearing on the treatment step, the claim is deemed indefinite as treating a subject known to have cancer with anti-cancer therapy appears to provide no advantage over that which is common sense.
Clarification is required.
Claim 64 is indefinite for reciting a trademarked product, “PROTAC.” A trademark does not identify the product, but the source of the product, whose formulation can be altered as well as being proprietary. Therefore, metes and bounds of such a trademark in a claim and indefinite. Applicants must remove all additional trademarks recited in the claim.
Claim 64 is also indefinite for reciting, “ALK-targeted therapy being tested in a clinical trial”, and similar phrase. Metes and bounds of a therapy being tested in a clinical trial is vast and unlimited and changes over time. Therefore, the metes and bounds are not definite.
Claim 70 is indefinite for reciting recitation of trial drugs, such as PLB1003 because such drug’s formulation is not concrete and may change, rendering the metes and bounds of the claim indefinite. All such drugs and their recitations should be removed from the claim.
Claims 67 and 70 are also indefinite by way of their dependency on claim 64.
Claims 64, 67, 70, 170, 177, and 197 are also indefinite by way of their dependency on claim 63.
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 63, 64, 67, 70, 74, 177, and 197 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 analysis is limited to the extent of the elected species for the present rejection.
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 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 claims embrace the detection of genus of nucleic acid fusion molecules which occur between ALK and NRP or its encoded fusion protein, wherein the detection of such fusion products aids to determine treatment of a cancer or delay its progress. Such nucleic acid fusion molecules are formed between two genes (in the present case, ALK and NRP) intrachromsomally, and the specification discloses that, “atypical fusions with non-canonical breakpoints” were identified (section [0104])
The specification discloses that such identified fusion products described from a sample of a cancer subject may aid to discover subjects “who are likely to respond to treatment with an anti-cancer therapy such as a targeted anti-cancer therapy” (section [0104])
The specification, however, discloses a single species of fusion molecule that are formed between ALK and NRP2 genes, namely having a 5’ breakpoint between exon 8 and 9 of NRP2 and 3’ breakpoint between exons 18 and 19 ALK (see Table 1, see also section [0184]) which have been identified from cancer leiomyosarcoma and soft tissue inflammatory myofibroblastic tumor (section [0184]).
Therefore, the specification fails to disclose a representative number of structurally diverse NRP2-ALK fusion sequence and its encoded fusion protein which is implicated with treatment outcome for a cancer of a subject, for a genus that includes other potential fusion products which form from different intrachromosomal rearrangement with different breakpoints, some of which are implicated and some of which are not implicated with cancer (i.e., non-functional), or treatment outcome thereof.
The specification fails to identify any structural characteristics that are shared among other potential NRP2-ALK fusion products that implicate a treatment outcome of a cancer subject so as to allow one of skill in the art to envision that applicants were in possession of such a genus.
Therefore, the single NRP2/ALK fusion sequence and its encoding protein is not representative of the claimed genus of any sequence of NRP2/ALK fusion nor the encoded proteins thereof.
Reduction to Drawing
The specification while showing some fusion sequences, doesn’t appear to identify any fusion sequences or products of NRP2/ALK correlated to cancer.
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 such NRP2/ALK fusion products that relate to cancer and treatment prognostics based thereon, 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 fusion products that not only exist (for which Applicants disclosed only a single species), but also that which provides prognostic value for treatment directed thereto.
The specification
Applicants have not disclosed enough number of species within the 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.
As well, in Juno Therapeutics, Inc. v. Kite Pharma, Inc. (10 F.4th 1330, 1337-42 (Fed. Cir. 2021), where the circuit court held that the disclosure of only two representative scFv species was insufficient to support an expansive genus where the specification did not provide representative species or structural characteristics allowing a skilled artisan to distinguish members falling within the claimed genus.
Specifically, the patent at issue, U.S. 7,446,190, asserted claims directed to a nucleic acid encoding a chimeric T cell receptor (better known as chimeric antigen receptor or CAR) comprising an intracellular CD3-zeta chain, a costimulatory signaling region that “comprises the amino acid sequence encoded by SEQ ID NO: 6,” and a “binding element that specifically interacts with a selected target.” The claimed embodiments included a CAR in which the binding element is a single chain anti-CD19 antibody (e.g., anti-CD19 scFv) and the CD3-zeta chain is the human zeta chain.
The court stated that two of the asserted claims were invalid because they “broadly claim all scFvs,” while the specification disclosing only two species as well as not providing any information about scFvs that would allow a person of ordinary skill in the art “to determine which scFvs will bind to which target. That scFvs in general were well-known or have the same general structure does not cure that deficiency” (pages 1339-40 of the decision).
Similarly, the claims are not simply directed to the fusion nucleic acid sequences formed between the genes NPR2 and ALK based on unknown number of breakpoints (and the encoded proteins thereof), but requires functional tie to therapeutic outcome thereto, the basis of which has not been provided by the specification.
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.
Claims 63, 64, 67, 70, 170, 177, and 197 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The present rejection pertains only to the elected species (i.e., NRP2/ALK fusion).
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.
Nature of the invention:
The nature of the invention relates to the correlation which exists between gene fusion products correlated to cancer and their ties to a subject’s predisposition to respond to anti-cancer treatment.
Amount of Direction/Guidance:
The specification provides guidance to the extent of identifying the presence of a single species of NRP2/ALK fusion product that purports to exist from a cancer subject. However, the specification provides no specific direction or guidance in relation to the findings and whether anti-cancer therapy directed thereto results in any benefit for dallying the progression of the cancer in the subject.
Absence of Working Example:
The specification provides no example relating to the presence of NRP2/ALK fusion sequence (or its encoded product) and any therapy directed thereto which results in the delay in progression of the cancer of a subject having said fusion product.
State of Prior art & Unpredictability:
A post filing publication by Maruta et al. (OncoTargets and Therapy, September 2024, vol. 17, pages 777-783) discloses the identification of a fusion product between EML4 and ALK from patients with NSCLC as well as what appeared to be a product that formed between NRP2 and ALK:
“Molecular profiling, Foundation One CDx, found EML4-ALK chimeric gene with multiple rearrangements”
“Further analysis of the molecular structure of EML4-ALK detected a fusion of ALK and EML4 as well as fusion of ALK and NRP2 … EML4-ALK was thought to encode an out-of-frame product, but the structure of the NRP2-ALK fusion was unable to be analyzed because the NRP2 region was not found no the gene body”
The artisans state that the purported fusion product was potentially formed from “an unusual insertion of a gene fragment derived from NRP2”, but concluding that the existence of such a fusion product (i.e., expressed ALK fusion transcript) could not be verified:
“The intronic sequence from both ALK and EML4 had been inserted between the exons of ALK and EML4 … possibly as a result of an unusual insertion of a gene fragment derived from NRP2, as indicated by panel sequencing results” (page 780)
“One CDx suggested that the inserted DNA might have been NRP2, but the RNA sequencing was unable to corroborate this hypothesis, and it is possible that intron mismapping might have given rise to an image splicing forgery or noise” (page 781, bottom)
Unpredictability of art and Conclusion:
In view of the above factors, and in view of the unpredictability that exists when assigning markers and disease correlation with the combination of absence of examples that demonstrate a positive correlation between NRP2/ALK fusion in a subject’s sample and their responsiveness to drugs in delaying the progression of cancer, one of ordinary skill in the art could not make and use the claimed invention without undue experimentation.
Conclusion
No claims are allowed.
The elected species utilizing ALK/NRP2 fusion sequence and its encoded product related to cancer is free of prior art, but stand rejected based on a substantive rejection under 112, 1st paragraph.
AU 2018201701 A1, published 2018 discloses the relevance of subgenomic intervals of NRP2 gene as being implicated with cancer (page 27, bottom paragraph to page 28)1 as well as some fusion products relating to ALK (with EML4, see page 112, for example), but fails to disclose or provide any suggestion of a fusion sequence between NRP2 and ALK.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/YOUNG J KIM/Primary Examiner
Art Unit 1637 September 12, 2026
/YJK/
1 The document is not provided due to size limitation, but available for view on patents.google.com
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