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 .
Detailed Action
This action is in response to the papers filed November 20, 2025.
Amendments
Applicant's amendments, filed November 20, 2025, is acknowledged. Applicant has cancelled Claims 5, 7-10, 13-15, 17-21, 23, 27-29, 31, 34-49, 51, 53-55, and 57-58, and amended Claim 50.
Claims 1-4, 6, 11-12, 16, 22, 24-26, 30, 32-33, 50, 52, 56, and 59-60 are pending.
Election/Restrictions
Applicant has elected without traverse the following species, wherein:
i) the alternative toxin SEQ ID NO is SEQ ID NO:34, as recited in Claim 12;
ii) the alternative IL-13 domain SEQ ID NO is SEQ ID NO:29, as recited in Claim 3;
iii) the alternative transmembrane domain SEQ ID NO is SEQ ID NO:14, as recited in Claim 2;
iv) the alternative co-stimulatory domain SEQ ID NO is SEQ ID NO:23, as recited in Claim 4; and
v) the alternative CAR SEQ ID NO is SEQ ID NO:50, as recited in Claim 16.
Claims 1-4, 6, 11-12, 16, 22, 24-26, 30, 32-33, 50, 52, 56, and 59-60 are pending.
Claims 33, 50, 52, and 56 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1-4, 6, 11-12, 16, 22, 24-26, 30, 32, and 59-60 are under consideration.
Priority
This application is a 371 of PCT/US2021/021890 filed on March 11, 2021. Applicant’s claim for the benefit of a prior-filed application provisional application 62/988,199 filed on March 11, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on January 10, 2023, August 11, 2023, and November 20, 2025 that have been considered.
The information disclosure statements filed January 10, 2023 and August 11, 2023 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Allowable Subject Matter
1. The following is a statement of reasons for the indication of allowable subject matter:
Claim 16 recites SEQ ID NO:50.
A chimeric antigen receptor comprising the amino acid sequence of SEQ ID NO:50 appears free of the prior art.
Brown et al (WO 16/044811; Applicant’s own work; hereafter Brown-1; of record) is closest prior art for having disclosed an IL-13 CAR whose amino acid sequence (lower line) is 88% identical to instant SEQ ID NO:50 (upper line), said IL-13 CAR comprising:
i) the IL-13 domain amino acid sequence of instant SEQ ID NO:29 (bold, underlined);
ii) the transmembrane domain of instant SEQ ID NO:14 (bolded); and
iii) the co-stimulatory domain of instant SEQ ID NO:23 (underlined) as shown below:
GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIE
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIE
KTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFNGGGGSGGG
||||||||||||||||||||||||||||||||||||||||||||||||||||
KTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN--------
GSGGGGSMCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCRESKYGPPCPPCPAPEFE
|||||||||||||||||
-------------------------------------------ESKYGPPCPPCPAPEFE
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
FQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
FQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWV
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS-------------------
|||||||||||||||||||||||||||||||||||||||||
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSGGGKRGRKKLLYIFKQPFM
--------------------------GGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE
||||||||||||||||||||||||||||||||||
RPVQTTQEEDGCSCRFPEEEEGGCELGGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE
YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ
GLSTATKDTYDALHMQALPPR
|||||||||||||||||||||
GLSTATKDTYDALHMQALPPR
Applicant’s prior art IL-13 does not comprise a chlorotoxin domain, e.g. instant SEQ ID NO:34.
Amino acids 1-112 of SEQ ID NO:50 are the SEQ ID NO:29 IL-13 domain.
Amino acids 128-163 of SEQ ID NO:50 are the SEQ ID NO:34 chlorotoxin domain.
Amino acids 394-420 of SEQ ID NO:50 are the SEQ ID NO:14 transmembrane domain.
Amino acids 421-461 of SEQ ID NO:50 are the SEQ ID NO:23 co-stimulatory domain.
However, the claim suffers from 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and AIA 35 U.S.C. 103 issues. See discussions below.
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.
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.
2. Claims 2, 4, and 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.
As a first matter, the claims recite the phrase “an amino acid sequence selected from”, which renders the claims indefinite because the reference SEQ ID NO’s are each composed of a plurality of amino acid sequences or subsequences, respectively, and it is unclear to which sequence or subsequence “an amino acid sequence” the reference SEQ ID NO Applicant refers.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
As a second matter, English has two articles: ‘the’, and ‘a/an’.
‘the’ is a definite article, referring to a specific or particular noun; whereas, ‘a/an’ is an indefinite article, modifying non-specific or non-particular nouns.
The Directors Technology Center 1600 Memorandum, Nucleic Acid and Peptide Claim Interpretation: “A” and “The” (December 29, 2005) informs the TC1600 Examiners that the phrase “A nucleic acid comprising a nucleotide sequence of SEQ ID NO:1” encompasses nucleic acids that comprise any portion of SEQ ID NO:1; whereas, the phrase “A nucleic acid comprising the nucleotide sequence of SEQ ID NO:1” is directed only to nucleic acids that comprise the full length of SEQ ID NO:1.
The Examiner suggests amending the claims to instead recite “the amino acid sequence”. See, for example, Claim 3.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
3. Claims 26 and 32 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.
As a first matter, the claim fails to recite the object to which the therapeutically effective amount of cells are to be administered.
As a second matter, Claim 26 recites “a therapeutically effective amount”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
While it is clear that the cells are to “harbour” the nucleic acid encoding chimeric antigen receptor comprising a chlorotoxin domain and an IL-13 domain, the claim does not require said cells to express said CAR.
Contrast Claim 26 with Claim 60 that requires the human T or NK cells to express said CAR.
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the context of the method, be it in vitro cell culture or in vivo [parameter 1];
the type of subject human or non-human animal to be treated [parameter 2];
the type of cell, does not express or expresses, the CAR [parameter 3];
the effector cell dosage and/or effector cell:target cell ratio, be it in vitro or in vivo [parameter 4];
the administration route [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the cellular composition that, upon administration to the in vitro tissue culture or the in vivo subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
The claim fails to recite the object to which the therapeutically effective amount of cells are to be administered. The claim would appear to encompass in vitro tissue culture assays, as well as in vivo contexts, e.g. tumor xenograft non-human animal models.
Parameter 2
While it is clear that the cells are to be human T or NK cells, the claims suffer from a gap in the elements for failing to recite that the object to which said cells is/are to be administered is a human being.
To the extent the context of the method is in vivo, the claims are broad for reasonably encompassing an enormous genus of animal subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, mice, and rats.
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
The specification’s working example is directed to a tumor xenograft mouse animal model (e.g. pg 23, lines 5-14).
Parameter 3
While it is clear that the cells are to “harbour” the nucleic acid encoding chimeric antigen receptor comprising a chlorotoxin domain and an IL-13 domain, the claim does not require said cells to express said CAR.
Contrast Claim 26 with Claim 60 that requires the human T or NK cells to express said CAR.
Parameter 4
The claims are broad for failing to recite the dosage of the immune effector cells to be administered, alone and/or relative to the target number of the tumor cells (syn. effector cell:target cell ratio).
Kim et al (Adoptive Immunotherapy of Human Gastric Cancer with Ex Vivo Expanded T Cells, Arch. Pharm. Res. 33(11): 1789-1795, 2010) is considered relevant prior art for having taught that the amount of cytotoxicity of immune effector cells against target cells varies according to the E:T ratio (e.g. Figure 2, E:T ratios of 1:1, 3:1, 10:1, or 30:1; Figure 3a).
The specification discloses an in vitro culture with an E:T ratio of 1:1 (20,000 T cells: 20,000 target cells) (e.g. pg 25, lines 15-16) or 1:4 (4,000 T cells: 16,000 target cells) (e.g. pg 25, line 29).
The specification discloses an in vivo mouse tumor xenograft model into which 5x10^6 CAR T cells were administered (e.g. pg 23, line 15).
The specification discloses the immune effector cells may be administered as a single dose, or repeated dosing (e.g. pg 4, lines 14-15; pg 8, line 14).
The specification discloses the immune effector cell population is heterogeneous, e.g. not more than 4% CD8+ cells (e.g. pg 5, line 32), or not more than 20% central memory T cells (e.g. pg 5, line 25).
Parameter 5
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
The specification discloses intraperitoneal or intravenous injection of the CAR T cells (e.g. pg 23, lines 14-15).
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question:
A therapeutically effective amount to do what?
The claim(s) also denote(s) that there is an amount of the cellular composition that, upon administration to the in vitro tissue culture or the in vivo subject, is not, in fact, “a therapeutically effective amount”.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the immune cells must be administered to the target cells, be they in vitro or in vivo, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses, for example:
For example:
the target neuroectodermal or glioma cancer includes, but is/are not limited to a glioblastoma, primary brain tumors and gliomas (glioblastoma multiforme WHO Grade IV, anaplastic astrocytoma, WHO Grade III, low-grade astrocytoma WHO Grade II, pilocytic astrocytoma WHO Grade I, other ungraded gliomas, oligodendroglioma, gliosarcoma, ganglioglioma, meningioma, ependymona), neuroectodermal tumors (medulloblastoma, neuroblastoma, ganglioneuroma, primitive neuroectodermal tumors, small cell lung carcinoma, Schwannoma), other brain tumors (epidermoid cysts, brain tumors of unknown pathology, pituitary gland of glioblastoma multiforme, and metastatic tumors to brain of unknown tissue origin) (e.g. pg 3, line 28-pg 4, line 4; pg 19, lines 15-23);
the phenotypic result may be avoiding cytokine storm or off-target toxicity (e.g. pg 16, line 13);
the phenotypic result may be killing tumor cell lines in vitro (e.g. pg 18, line 5);
the phenotypic result may be elimination of antigen-positive disease or extension of overall survival (e.g. pg 19, lines 8-9); and
the phenotypic result may be a reduction in ascites, labored or difficult breathing, apparent weight loss, impaired mobility, or other symptom(s) associated with disease (e.g. pg 23, lines 19-21).
Lamb et al (WO 18/107134) is considered relevant prior art for having disclosed a method of treating cancer in a subject comprising the step of administering CAR-T cells to the subject, wherein “treating” includes, but is not limited to, phenotypic results such as reducing cancer, inhibiting cancer, reducing tumor mass size or volume, a decrease in the number of metastasized tumors, elimination of tumor growth or regrowth (e.g. pg 12, lines 13-16; pg 35, lines 4-6).
Davila et al (U.S. 2023/0229520) is considered relevant prior art for having disclosed a method of treating cancer in a subject comprising the step of administering CAR-T cells to the subject, wherein “treating” includes, but is not limited to, phenotypic results such as curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder;
improvement of the disease, condition, or disorder;
removal of the cause of the disease, condition, or disorder;
relief of symptoms, rather than curing, the disease, condition, or disorder;
minimizing or partially or completely inhibiting development of the disease, condition, or disorder; or
supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder [0039, 41].
The term “preventing” is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025).
If there are multiple ways to measure “therapeutically effective dose”, to wit, concentration, time after administration, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the CAR T or NK dosage administered is a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
4. Claims 26 and 32 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.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
As a first matter, the claim fails to recite the object to which the therapeutically effective amount of cells are to be administered.
As a second matter, Claim 26 recites “a therapeutically effective amount”.
While it is clear that the cells are to “harbour” the nucleic acid encoding chimeric antigen receptor comprising a chlorotoxin domain and an IL-13 domain, the claim does not require said cells to express said CAR.
Contrast Claim 26 with Claim 60 that requires the human T or NK cells to express said CAR.
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the context of the method, be it in vitro cell culture or in vivo [parameter 1];
the type of subject human or non-human animal to be treated [parameter 2];
the type of cell, does not express or expresses, the CAR [parameter 3];
the effector cell dosage and/or effector cell:target cell ratio, be it in vitro or in vivo [parameter 4];
the administration route [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claim(s) also denote(s) that there is an amount of the cellular composition that, upon administration to the in vitro tissue culture or the in vivo subject, is not, in fact, “a therapeutically effective amount”.
Parameter 3
The claims are broad for reasonably encompassing an enormous genus of functionally different CAR-T cell populations, and dosages to be administered to the subject, per the arbitrary and subjective discretion of the attending physician, relative to age, weight, tumor size, extent of infection or metastasis, condition of the subject.
Figueroa et al (Chimeric Antigen Receptor Engineering: A Right Step in the Evolution of Adoptive Cellular Immunotherapy, Int. J. Immunol. 34: 154-187, 2015) is considered relevant prior art for having taught that while CAR immunotherapy shares the common goal of specifically targeting and eradicating target disease cells, the different strategies exploit distinct components of the immune system and their generalized success has been hindered by the paucity of specific antigen targets, resulting in suboptimal responses and unpredictable toxicities (e.g. Abstract).
CARs are designed to comprise intracellular co-stimulatory signaling domains that may promote sequential rounds of T-cell proliferation. T-cell activation and proliferation requires signaling through both the T-cell receptor and co-stimulatory molecules. Once target antigens are recognized, the function and survival of the CAR-T cells depends on the activation of chimeric co-stimulatory receptors (e.g. pg 159). However, some CAR designs demonstrate low proliferative capacity, leading to apoptosis, consequent anergy, and only transient persistence, resulting in limited efficacy against the target cell (e.g. pg 158).
Other factors that contribute to poor efficacy includes the T-cell’s functional characteristics (e.g. pg 158, para 2). Marked differences in phenotypic and differentiation states suggests that distinct populations of T-cells may have specific uses. Characteristics such as suitability for ex vivo expansion, length of engraftment, antigen-dependent proliferative capacity, migratory capability, susceptibility to immunoediting and therapeutic efficacy are critical when defining “optimal” T-cell populations for CAR engineering and clinical use. Nonetheless, selecting defined T-cell subpopulations for ACI engineering purposes adds complexity, difficulty and cost to an already expensive process. an already expensive process.
One of the major unresolved issues in the clinical application of CAR-T cell therapy is the optimal number of cells required for a robust antitumor effect. The use of T cells with restricted proliferative capacity will require much higher “cellular doses” than the use of less differentiated T-cells with greater plasticity and replicative capacity, which also affects the degree of engraftment, persistence, replication, self-renewal, differentiation, and anti-target cells activity, as different T-cell types have different intrinsic properties, being more or less efficacious (e.g. pgs 167-168), which adds complexity, difficulty, and cost to an already expensive process.
Clinical experience has demonstrated suboptimal homing of effector cells to solid tumors, limited engraftment, and generally disappointing results, including adverse events related to on-target/off-tumor effects and no significant clinical response (e.g. pg 170).
The most common systemic toxicity associated with CAR-T cells relates to the systemic inflammatory response, and can result in anaphylaxis, which may be fatal (e.g. pg 172).
Parameter 6
Brown-1 (WO 16/044811; Applicant’s own work; of record) is considered relevant prior art for having disclosed that intravenous administration of IL-13 CAR T cells provided no therapeutic effect against intracranially injected glioblastoma tumors in a mouse tumor xenograft model (e.g. Example 9, [0088]). Rather, intracranial administration of the CAR T cells provided robust therapeutic efficacy.
The claims fail to recite, and the specification fails to disclose, the necessary structure/function/action-taking step(s) nexus between the combination of each of:
the context of the method, be it in vitro cell culture or in vivo [parameter 1];
the type of subject human or non-human animal to be treated [parameter 2];
the type of cell, does not express or expresses, the CAR [parameter 3];
the effector cell dosage and/or effector cell:target cell ratio, be it in vitro or in vivo [parameter 4];
the administration route [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
At best, the specification supports a method of treating peripheral, extracranial, glioblastoma in a xenograft mouse tumor model, the method comprising the step of administering by intravenous or intraperitoneal injection to said mouse at least 5x10^6 Cltx/IL-13 CAR T cells.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
5. Claims 26 and 32 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 peripheral, extracranial, glioblastoma in a xenograft mouse tumor model, the method comprising the step of administering by intravenous or intraperitoneal injection to said mouse at least 5x10^6 Cltx/IL-13 CAR T cells,
does not reasonably provide enablement for the necessary structure/function/action-taking step(s) nexus between the combination of each of:
the context of the method, be it in vitro cell culture or in vivo [parameter 1];
the type of subject human or non-human animal to be treated [parameter 2];
the type of cell, does not express or expresses, the CAR [parameter 3];
the effector cell dosage and/or effector cell:target cell ratio, be it in vitro or in vivo [parameter 4];
the administration route [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
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 Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejections.
Parameter 6
Brown-1 (WO 16/044811; Applicant’s own work; of record) is considered relevant prior art for having disclosed that intravenous administration of IL-13 CAR T cells provided no therapeutic effect against intracranially injected glioblastoma tumors in a mouse tumor xenograft model (e.g. Example 9, [0088]). Rather, intracranial administration of the CAR T cells provided robust therapeutic efficacy.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that there are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
The claims fail to recite, and the specification fails to disclose, a first CAR T cell dosage [parameter 4] of the heterogeneous population of immune effector cells [parameter 3], including those cells that comprise, but do not express, the CAR, administered via a first administration route, e.g. subcutaneously [parameter 5], to a first subject, e.g. a pig [parameter 2], that is necessarily and predictably able to prevent glioblastoma [parameter 6], as opposed to a second CAR T cell dosage [parameter 4] of the heterogeneous population of immune effector cells [parameter 3], including those cells that comprise, but do not express, the CAR, administered via a second administration route, e.g. inhalation or suffusion [parameter 5], to a second subject, e.g. a human [parameter 2], that is necessarily and predictably able to extend overall survival [parameter 6], for example.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
The claims fail to recite, and the specification fails to disclose, the structure/function/action-taking step(s) nexus between the combination of each of:
the context of the method, be it in vitro cell culture or in vivo [parameter 1];
the type of subject human or non-human animal to be treated [parameter 2];
the type of cell, does not express or expresses, the CAR [parameter 3];
the effector cell dosage and/or effector cell:target cell ratio, be it in vitro or in vivo [parameter 4];
the administration route [parameter 5]; and
the phenotypic response to be achieved [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of the broadly recited genus of neuroectodermal or glioma cancer, including, but not limited to, a glioblastoma, primary brain tumors and gliomas (glioblastoma multiforme WHO Grade IV, anaplastic astrocytoma, WHO Grade III, low-grade astrocytoma WHO Grade II, pilocytic astrocytoma WHO Grade I, other ungraded gliomas, oligodendroglioma, gliosarcoma, ganglioglioma, meningioma, ependymona), neuroectodermal tumors (medulloblastoma, neuroblastoma, ganglioneuroma, primitive neuroectodermal tumors, small cell lung carcinoma, Schwannoma), other brain tumors (epidermoid cysts, brain tumors of unknown pathology, pituitary gland of glioblastoma multiforme, and metastatic tumors to brain of unknown tissue origin),
wherein said treatment necessarily and predictably achieves a real-world, clinically meaningful phenotypic result including, but not limited to, avoiding cytokine storm or off-target toxicity, killing tumor cells, elimination of antigen-positive disease or extension of overall survival, a reduction in ascites, labored or difficult breathing, apparent weight loss, impaired mobility, or other symptom(s) associated with disease.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a method of treating peripheral, extracranial, glioblastoma in a xenograft mouse tumor model, the method comprising the step of administering by intravenous or intraperitoneal injection to said mouse at least 5x10^6 Cltx/IL-13 CAR T cells, is proper.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Claim Rejections - 35 USC § 103
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 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 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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
6. Claims 1-4, 16, 22, 30, 24-26, 32, and 59-60 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Brown et al (WO 16/044811; Applicant’s own work; hereafter Brown-1; of record) in view of Barish et al (WO 17/066481; Applicant’s own work; hereafter Brown-2; of record), Nabors (Targeted Molecular Therapy for Malignant Gliomas, Current Treatment Options in Oncology 5: 519-526, 2004; of record), and Zah et al (T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells, Cancer Immunol. Res. 4(6): 498-508, 2016).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 1-4 and 16, Brown-1 is considered relevant prior art for having disclosed a chimeric antigen receptor comprising:
i) an IL-13 domain;
ii) a spacer;
iii) a transmembrane domain;
iv) a co-stimulatory domain; and
v) a CD3zeta signaling domain (e.g. Figure 1).
Brown-1 disclosed wherein the IL-13 chimeric antigen receptor is useful for the treatment of glioma (e.g. [0054-55]).
Brown-1 disclosed an IL-13 CAR whose amino acid sequence (lower line) is 88% identical to instant SEQ ID NO:50 (upper line), said IL-13 CAR comprising the IL-13 domain amino acid sequence of instant SEQ ID NO:29 (bold, underlined), the transmembrane domain of instant SEQ ID NO:14 (bolded), and the co-stimulatory domain of instant SEQ ID NO:23 (underlined) as shown below:
GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIE
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIE
KTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFNGGGGSGGG
||||||||||||||||||||||||||||||||||||||||||||||||||||
KTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN--------
GSGGGGSMCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCRESKYGPPCPPCPAPEFE
-------------------------------------------ESKYGPPCPPCPAPEFE
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ
FQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
FQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWV
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS-------------------
|||||||||||||||||||||||||||||||||||||||||
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSGGGKRGRKKLLYIFKQPFM
--------------------------GGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE
EEEEGGCELGGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE
YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ
GLSTATKDTYDALHMQALPPR
|||||||||||||||||||||
GLSTATKDTYDALHMQALPPR
Instant Claim 16 does not require the entirety of SEQ ID NO:50. As shown above, Brown-1 disclose an IL-13 CAR comprising one or more amino acid sequences inherently and naturally present in SEQ ID NO:50.
See also 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection above.
Brown-2 is considered relevant prior art for having disclosed a chimeric antigen receptor comprising:
i) a chlorotoxin (Cltx) domain;
ii) a linker;
iii) an antigen-binding domain;
iv) a spacer;
v) a transmembrane domain;
vi) a co-stimulatory domain; and
vii) a CD3zeta signaling domain (e.g. Figure 1).
Brown-2 disclosed wherein the chlorotoxin-containing chimeric antigen receptor is useful for the treatment of glioma (e.g. Abstract; [0019]).
While Brown-2 disclosed that examples of CAR tumor targeting domains include IL-13 CARs (e.g. [001]), Brown-2 do not disclose a reduction to practice of linking an IL-13 domain to a cytotoxin.
Nabors is considered relevant prior art for having taught that:
a) like Brown-1, the IL-13 receptor is expressed at high levels on glioma tumors (e.g. pg 521);
b) IL-13 fused to a cytotoxin has been used for the treatment of gliomas (e.g. pg 521); and
c) chlorotoxin binds specifically and with high affinity to tumors of the central nervous system, including gliomas (e.g. pg 522).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will’be knowledg’able and well-read in the relevant literature and have the practical experience in molecular biology, cancer biology, and the creation of chimeric antigen receptors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a pe“son of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ”__, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be“able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "”he inferences and creative steps that a person of“ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Zah et al is cons”dered relevant prior art for having taught the synthesis of a bispecific chimeric antigen receptor comprising a first (e.g. anti-CD19) and second (e.g. anti-CD20) target binding domains, wherein the first and second target binding domains may be in either order, CD19xCD20 or CD20xCD19 (e.g. Figure 1c).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the IL-13 chimeric antigen receptor to further comprise a chlorotoxin with a reasonable expectation of success because Applicant themselves (Brown-2) disclosed chlorotoxin-containing CARs for the treatment of glioma, examples of which include CAR tumor targeting domains include IL-13 CARs, and Nabors et al taught that:
a) like Brown-1, the IL-13 receptor is expressed at high levels on glioma tumors (e.g. pg 521);
b) IL-13 fused to a cytotoxin has been used for the treatment of gliomas (e.g. pg 521); and
c) chlorotoxin binds specifically and with high affinity to tumors of the central nervous system, including gliomas (e.g. pg 522).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first CAR glioma tumor targeting domain with a second CAR glioma tumor targeting domain, i.e. IL-13, in a chlorotoxin-containing CAR with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its sui“ability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substitu”ing equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first CAR glioma tumor targeting domain with a second CAR glioma tumor targeting domain, i.e. IL-13, in a chlorotoxin-containing CAR because:
a) Applicant themselves previously disclosed IL-13-containing CARs for the treatment of glioma;
b) chlorotoxin-containing CARs are useful for the treatment of glioma, and
c) IL-13-toxin fusions were previously recognized to be useful for the treatment of glioma.
It is proper to "take account of the inferences and creative steps “hat a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, ”741,82 U’PQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 2, as discussed above, Brown-1 disclosed wherein the CAR comprises a CD28 transmembrane domain comprising the amino acid sequence of instant SEQ ID NO:14.
Brown-2 also disclosed wherein the CAR comprises a CD28 transmembrane domain comprising the amino acid sequence of instant SEQ ID NO:14 (e.g. Table 2), as shown below:
FWVLVVVGGVLACYSLLVTVAFIIFWV
|||||||||||||||||||||||||||
FWVLVVVGGVLACYSLLVTVAFIIFWV
With respect to Claim 4, as discussed above, Brown-1 disclosed wherein the CAR comprises a CD28gg* co-stimulatory domain comprising the amino acid sequence of instant SEQ ID NO:23.
Brown-2 also disclosed wherein the CAR comprises a CD28gg* co-stimulatory domain comprising the amino acid sequence of instant SEQ ID NO:23 (e.g. Table 3), as shown below:
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
|||||||||||||||||||||||||||||||||||||||||
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
With respect to Claim 12, Brown-2 disclosed wherein the chlorotoxin domain (e.g. [005], lower line) comprises the amino acid sequence of SEQ ID NO:34 (upper line), as shown below:
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
||||||||||||||||||||||||||||||||||||
MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR
With respect to Claim 6, Brown-2 disclosed wherein the Cltx-CAR may further comprise additional target binding domains, wherein the first and second target binding domains are separated by a linker domain comprising 1-10 amino acids (e.g. [007]).
X et al taught/disclose the presence of a linker of 3-50 amino acids between the first antigen-binding domain and the second antigen-binding domain of a bi-specific CAR.
Zah et al taught wherein the bispecific CAR comprises a linker domain of about 20 amino acids between the first and second target binding domains (e.g. pg 500, col. 2, (G4S)4 linker).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 11, those of ordinary skill in the art immediately recognize that there are only two options: A before B, and B before A.
Furthermore, Zah et al taught the synthesis of a bispecific chimeric antigen receptor comprising a first (e.g. anti-CD19) and second (e.g. anti-CD20) target binding domains, wherein the first and second target binding domains may be in either order, CD19xCD20 or CD20xCD19 (e.g. Figure 1c).
It would have been obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.”
One of ordinary skill in the art would understand how to design bi-specific chimeric antigen receptors, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success. The number of possible configurations from which to choose, to wit, two (2), is neither astronomical nor insurmountable, and given the guidance of Zah et al (bi-specific CAR), it would be only routine experimentation to determine which configuration, A before B, or B before A, yielded a desired result.
With respect to Claim 22, Brown-1 disclosed an expression vector comprising the nucleic acid encoding said IL-13-CAR (e.g. [009]).
Brown-2 disclosed an expression vector comprising the nucleic acid encoding said Cltx-CAR (e.g. [009]).
With respect to Claims 24 and 60, Brown-1 disclosed a population of human T or NK cells genetically modified to comprise and express the nucleic acid encoding said IL-13-CAR (e.g. [009-10]).
Brown-2 disclosed a population of human T cells genetically modified to comprise and express the nucleic acid encoding said Cltx-CAR (e.g. [009-10]).
With respect to Claim 25, Brown-1 disclosed the population of human T cells comprise central memory T cells (e.g. [009-10]).
Brown-2 disclosed the population of human T cells comprise central memory T cells (e.g. [009-10]).
With respect to Claim 30, Brown-1 disclosed a method of preparing IL-13-CAR human T cells, the method comprising the step of transducing a population of autologous or allogeneic human T cells (e.g. [0010]) with an expression vector encoding the nucleic acid encoding said IL13-CAR (e.g. [009]).
Brown-2 disclosed a method of preparing IL-13-CAR human T cells, the method comprising the step of transducing a population of autologous or allogeneic human T cells (e.g. [0010]) with an expression vector encoding the nucleic acid encoding said Cltx-CAR (e.g. [009]).
With respect to Claims 26 and 32, Brown-1 disclosed a method of treating glioblastoma in a tumor xenograft mouse model, the method comprising the step of administering by intravenous or intracranial injection a population of human T cells genetically modified to express the IL13-CAR (e.g. Example 9).
Brown-2 disclosed a method of treating glioblastoma in a tumor xenograft mouse model, the method comprising the step of administering by an undisclosed route a population of human T cells genetically modified to express the Cltx-CAR (e.g. Example 12).
Zah et al taught a method of treating cancer in a tumor xenograft mouse model, the method comprising the step of administering by intravenous injection a population of human T cells genetically modified to express a bi-specific CAR (e.g. pg 499, col’s 1-2, Methods).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
7. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638