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 .
1. Claims 1-16 are pending and being examined.
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.
2. Claims 1-4 and 6-16 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is drawn to a chimeric antigen receptor (CAR) comprising an extracellular binding domain which comprises a structure based on a GAS6 protein comprising an amino acid sequence set forth in SEQ ID NO: 1 or a fragment thereof and is able to specifically bind to a GAS6 receptor. Thus, claim 1 encompasses any amino acid sequence with no defined basis on a GAS6 protein comprising any (“an”) amino acid sequence found in (“set forth in”) SEQ ID NO:1 or fragments thereof. The claims encompass a vast genus of undefined extracellular binding domains required to specifically bind to a GAS6 receptor (i.e., AXL).
Dependent claim 2 recites the extracellular domain comprises a GAS6 protein or fragment thereof which has any (“an”) amino acid sequence found in (“as shown in”) SEQ ID NO:1, or has any (“an”) amino acid sequence found in (“as shown in”) positions 1-678 of SEQ ID NO:1 (claim 2). Claim 2 encompasses a vast genus of undefined amino acid sequences required to bind to GAS6 receptor, and that can comprise as few as two consecutive amino acids found anywhere in SEQ ID NO:1.
Claim 3 further recites various GAS6 protein sequences on which the CAR extracellular binding domain is “based” but does not provide any critical, identifiable sequence structure for the extracellular binding domain to bind GAS6 receptor.
Claim 4 recites the CAR formula structure of L-EB-H-TM-C-CD3ζ-RP but does not define or identify the sequence structure of the “EB” extracellular binding domain required to bind the GAS6 receptor.
Claim 12 further requires an immune cell expressing the CAR to prevent and treat diseases related to abnormal GAS6 receptor expression.
Claim 16 recites the extracellular binding domain comprises any (“an”) amino acid sequence found in (“as shown in”) positions 261-678 of SEQ ID NO:1. Claim 16 encompasses a vast genus of undefined amino acid sequences found anywhere in SEQ ID NO:1 that are required to bind to GAS6 receptor.
Thus, the claims identify the extracellular binding domain of the CAR by function only, where the function is to bind GAS6 protein receptor, and dependent claims require treating/preventing a disease associated with abnormal GAS6 receptor expression. No identifiable, shared extracellular binding domain structure critical to performing the claimed functions is recited for the claimed genus.
The instant specification discloses producing a CAR that binds to a GAS6 receptor comprising an extracellular binding domain comprising at least amino acid residues 261-678 of SEQ ID NO:1 (Figure 1; Examples). It appears amino acid residues 261-678 of SEQ ID NO:1 represent the critical sequence structure shared across the claimed genus for binding to GAS6 receptor.
Thus, the instant specification describes a single species of extracellular binding domain sequence that is representative of the claimed genus. The specification fails to disclose any other extracellular binding domains or sequences “based on” SEQ ID NO:1 or fragments thereof, or sequences found in SEQ ID NO:1 that possess the function of binding to GAS6 receptor.
To provide adequate written description and evidence of possession of the claimed extracellular binding domain genus, the instant specification can structurally describe representative extracellular binding domains that function to bind a GAS6 receptor, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the extracellular binding domain function: “specifically bind a GAS6 receptor”. Other than for amino acids 261-678 of SEQ ID NO:1, the instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only a single exemplary core, critical extracellular binding domain sequence that functions as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the extracellular binding domain does, rather than what it is. Other than for amino acids 261-678 of SEQ ID NO:1, the specification fails to provide any structural features coupled to the claimed functional characteristics. Other than for proteins comprising amino acids 261-678 of SEQ ID NO:1, the instant specification fails to describe a representative number of extracellular binding domain sequences for the vast genus of extracellular binding domains that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
Although Applicants may argue that it is possible to screen for extracellular binding domains that bind to a GAS6 receptor and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n 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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future extracellular binding domains yet to be discovered that may function as claimed. A “GAS6 receptor” provides no information about the structure of an extracellular binding domain that binds to it.
Given the lack of representative examples to support the full scope of the claimed extracellular binding domain required to make the claimed CAR, immune cell, and to practice the claimed methods, and given the lack of reasonable structure-function correlation with regards to the unknown sequences in the extracellular binding domain that provide GAS6 receptor-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the vast genus of extracellular binding domains that bind a GAS6 receptor that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend claim 1 to require the extracellular binding domain comprise SEQ ID NO:1 or at least amino acids 261-678 of SEQ ID NO:1.
3. Claims 12-15 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 of treating a disease related to the abnormal expression of GAS6 receptor AXL encompassing cancers by administering the claimed immune cell to a subject in need thereof, does not reasonably provide enablement for a method of preventing said disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are drawn to methods of preventing diseases, particularly cancers, that abnormally express GAS6 receptor by administering an engineered immune cell expressing the claimed CAR to a subject in need thereof.
The specification discloses in vitro killing effects of a GAS6-CAR on various cancer cell lines by % cell lysis (Figures 3 and 5), however, none of the results demonstrate that the GAS6-CAR lyse 100% of the cancer cells and would be capable of preventing cancer in a subject as claimed. A high quantity of experimentation would be required to test the invention in subjects having cancer to determine if prevention could be predictably achieved.
A search of relevant art does not reveal support for cancer prevention by administering an immune cell expressing a CAR comprising an extracellular binding domain that comprises a GAS6 sequence and binds to a GAS6 receptor.
One cannot extrapolate the disclosure of the specification to the scope of the claims because the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer or have had cancer. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and Iink those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification. A high quantity of experimentation would be required to determine if and what cancers the claimed CAR-expressing cell could prevent.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the claimed immune cell comprising the claimed CAR will predictably function to prevent cancer as claimed.
Therefore, in view of the novel nature of the invention, the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Examiner Suggestion: Delete the phrase “preventing and/or” from claim 12.
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.
4. Claims 1-16 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 recites the extracellular binding domain comprises a structure “based on” a GAS6 protein comprising an amino acid sequence set forth in SEQ ID NO:1 or a fragment thereof. Claim 1 is unclear how the extracellular binding domain structure is “based on” the claimed GAS6 protein. What basis? The metes and bounds of the claimed invention cannot be determined.
Dependent claims are rejected for encompassing the rejected limitations of claim 1.
Claims 2 and 3: A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by “such as” and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd.App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
In the present instance, claim 2 recites the broad recitation of “has an amino acid sequence as shown in SEQ ID NO:1 or has an amino acid sequence as shown in positions 1 to 678”, and the claim also recites “(preferably positions 31-678, more preferably positions 118-678, and more preferably positions 261-678)”, which is the narrower statement of the range/limitation.
In the present instance, claim 3 recites the broad recitation of “replacing, deleting, altering or inserting one or more amino acid residues, or adding 1-30 amino acid residues”, and the claim also recites “preferably 1-10 amino acid residues, more preferably 1-5 amino acid residues” which is the narrower statement of the range/limitation.
Additionally claim 3 recites the broad recitation of “the obtained amino acid sequence has a sequence identity of ≥85%”, and the claim also recites in parenthesis “(preferably ≥90%, more preferably ≥95%, such as ≥96%, ≥97%, ≥98%, or ≥99%)” which is the narrower statement of the range/limitation.
Claim 2 recites a phrase in parenthesis “(preferably positions 31-678, more preferably positions 118-678, and more preferably positions 261-678)” which renders the claim indefinite because it is unclear whether the limitations in the parenthesis are part of the claimed invention.
Claim 3 recites the phrase "such as" which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 3 recites a phrase in parenthesis “(preferably ≥90%, more preferably ≥95%, such as ≥96%, ≥97%, ≥98%, or ≥99%)” which renders the claim indefinite because it is unclear whether the limitations in the parenthesis are part of the claimed invention.
Claim 3 recites the amino acid sequence of the GAS6 protein is: “(ii) on the basis of the sequence shown in positions 261-678 of the sequence of SEQ ID NO:1, an amino acid sequence obtained by replacing, deleting, altering or inserting one or more amino acid residues, or adding 1-30 amino acid residues, preferably…and the obtained sequence has the same or similar function as the sequence in (i).” Claim 2 is unclear how the GAS6 amino acid sequence is “on the basis of” the recited list of amino acid positions or obtained amino acids that function the same or as similar as the sequence in (i). Based on those amino acid positions and sequence how? The metes and bounds of the claimed invention cannot be determined.
Dependent claims are rejected for encompassing the rejected limitations of claim 1.
5. Conclusion: No claim is allowed. The closest prior art made of record but not relied upon is Zhao et al (BioMed Research International, 2020, Article ID 4795171, 13 pages). Zhao teaches AXL-CAR-T cells administered to treat breast cancer, wherein the CAR comprises an extracellular binding domain comprising an scFv that binds to AXL, a GAS6 receptor (Figure 1):
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Zhao does not teach or suggest the CAR binding domain comprises GAS6 SEQ ID NO:1 or amino acid residues 261-678 of SEQ ID NO:1.
6. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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