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 .
Claims 1-18 are pending and will be examined on the merits.
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 3-4 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.
Regarding claims 3-4, each recitation of the phrase "preferably" each independently render its respective claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Note: for examination both claims 3 and 4 will be examined with respect a CAR comprising SEQ ID NO:1 or an amino acid sequence comprising amino acid residues at positions 58-273 of SEQ ID NO: 1
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 4 is 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.
Note: this rejection only applies to (ii) of claim 4.
Claim 4 is directed to a CAR comprising a LOX1 protein or fragment thereof, with the LOX1 component of the CAR possessing the required function of binding a LOX1 receptor by way of dependency on claim 1. With respect to the structure of the LOX1 component of the instant claimed CAR, claim 4 is directed to LOX1 proteins and fragments thereof having up to 15% amino acid sequence variation compared to AAs 58-273 of SEQ ID NO: 1 obtained by replacing, deleting, altering or inserting one or more amino acid residues. Instant claim 4 provides no guidance or limitations regarding which amino acids are permitted to be targeted for alteration or which alterations are permitted in order to arrive at the claimed sequence having up to 15% amino acid sequence variance compared to AAs 58-273 of SEQ ID NO: 1 capable of performing the required function of binding a LOX1 receptor. As such, instant claim 4 is directed to all possible amino acid sequence having at least 85% sequence identity to AAs 58-273 of SEQ ID NO: 1 that are capable of performing the recited function of binding a LOX1 receptor.
With respect to the species disclosed in the instant Specification, the instant Specification discloses four species of LOX1-derived binding domains capable of performing the recited function of binding a LOX1 receptor, all of which are contiguous amino acid sequences from SEQ ID NO:1, which are: 1) AAs 1-273 of SEQ ID NO: 1, 2) AAs 38-273 of SEQ ID NO: 1, 3) AAs 58-273 of SEQ ID NO: 1 and 4) AAs 151-273 of SEQ ID NO: 1 (Specification, p 3, lines 15-21). The instant Specification does not, however, disclose any variants of any contiguous sequence of SEQ ID NO: 1 having up to 15% amino acid sequence variation compared to the parental sequence derived from SEQ ID NO: 1 obtained by replacing, deleting, altering or inserting one or more amino acid residues capable of performing the recited function of binding a LOX1 receptor.
Ahmad (Ahmad, et al., Adv Med, Den and Health Sci, 2021 4(4):37) teaches on the subject of molecular docking, which is a method of predicting the binding between a ligand and a receptor, which is often a protein with a known 3D structure, by identifying appropriate positions of the molecules with each other when bound together for forming a stable complex (Ahmad, Abstract). Ahmad teaches that there are multiple general methods of docking, which make differing assumptions about the protein and the ligand and that these include: 1) the rigid ligand/rigid receptor approach, 2) the flexible ligand/rigid receptor approach, 3) the flexible ligand/flexible receptor approach and 4) the local move Monte Carlo approach (Ahmad, p 38, ¶ 4 – p 39, ¶ 2) Ahmad teaches that applications of molecular docking have included the identification of compounds capable of binding to and inhibiting the SARS-CoV-2 protease Mpro (Ahmad, p 41, ¶3).
The written description requirement may be satisfied in one of two ways: by disclosure of a representative number of species or by establishment of structure/function correlation (See MPEP § 2163).
As stated and articulated above, the instant disclosure does disclose four species of LOX1-derived binding domains capable of performing the required function of binding a LOX1 receptor, all of which are contiguous amino acid sequences of SEQ ID NO: 1 of varying lengths. However, the instant disclosure does not disclose any examples of species having up to 15% amino acid sequence variation compared to AAs 58-273 of SEQ ID NO: 1 (or any other contiguous AA sequence of SEQ ID NO: 1 disclosed) that is capable of performing the required function of binding a LOX1 receptor. When there is substantial variation within a genus, one must describe a sufficient variety of species to reflect the variation within that genus (See: MPEP § 2163(II)(3)(a)(ii)). As such, species disclosed in the instant specification are not sufficient to establish written description for the claimed genus as the disclosed species are only representative of the genera of LOX1-derived binding domains having 100% sequence identity to AAs 58-273 of SEQ ID NO: 1.
With respect to structure-function correlation, the teachings of Ahmad show that, at the time of filing, even predicting whether or not any given ligand will bind to any given protein requires knowing the structure of the protein, knowing the structure of the ligand and performing molecular docking calculations in order to predict whether or not the given ligand is likely to bind to the protein. This means that, at the time of filing, it was possible to a skilled artisan to use techniques such as molecular docking to determine if any given candidate variant sequence having up to 15% AA sequence variation compared to SEQ ID NO: 1 is likely to bind to any given LOX1 receptor, these techniques to not provide sufficient structure-function correlation to permit a skilled artisan to start with the fact that a structure comprises at least 85% sequence identity to instant SEQ ID NO: 1 and envision the required additional unrecited structure required to perform the required function of binding a LOX1 receptor.
There is nothing in the instant Specification to supplant this notion. Because the species disclosed are insufficient to be considered representative of any the scope of any of the genera encompassed in the rejected claims coupled with the lack of established structure/function correlation, claims 4 lacks written description and Applicant was not in possession of the invention as claimed.
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 (i.e., changing from AIA to pre-AIA ) 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, 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claim(s) 1-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Orentas (Orentas, et al., WO 2014/160627; Published 10/02/2024) in view of Cao (Cao, et al., FEBS Jounal 2019, 276:4909) and Kumar (Kumar, et al., (Canc. Lett. 2016; 374(1):156).
Orentas teaches on the subject of chimeric antigen receptors comprising extracellular binding domains recognizing CD276, nucleic acids encoding such CARs, expression vectors expressing such CARs and host cells/cell populations expressing such CARs (Orentas, Abstract). Orentas teaches that CD276 is expressed on a variety of human tumors and, as such, the anti-CD276 response elicited by the CARs of Orentas target and destroy cancer cells (Orentas, ¶ 0015). Regarding claim 6, Orentas teaches that SEQ ID NO: 74 of Orentas comprises intracellular and intracellular domains identical to the transmembrane and intracellular domain sequences of instant SEQ ID NO: 8 (Orentas, ¶ 0050).
MQLSQVSDLLTQEQANLTHQKKKLEGQISARQQAEEASQESENELKEMIETLARKLNEKSKEQMELHHQNLNLQETLKRVANCSAPCPQDWIWHGENCYLFSSGSFNWEKSQEKCLSLDAKLLKINSTADLDFIQQAISYSSFPFWMGLSRRNPSYPWLWEDGSPLMPHLFRVRGAVSQTYPSGTCAYIQRGAVYAENCILAAFSICQKKANLRAQTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
SEQ ID NO: 8 of the instant Application. The underlined portion corresponds to the transmembrane and intracellular domains of the CAR (identical to SEQ ID NO: 74 of Orentas) and the highlighted portion corresponds to the LOX1 extracellular binding domain (AAs 58-273 of SEQ ID NO: 1)
Regarding claims 7-9, Orentas teaches host cells comprising expression vectors (Orentas, claims 24-25), wherein said expression vector comprises nucleic acids encode the CARs of Orentas (Orentas, claims 20-24). Regarding claims 10 and 18, Orentas teaches that the host cell expressing the CAR of Orentas is a T cell (as such is an engineered immune cell) (Orentas, ¶ 0082) and that such host cells are administered in methods of treating methods of treating cancer expressing CD276 (note: reads on claims 12 and 16-17 because administering requires a pharmaceutical composition comprising a carrier comprising the engineered immune cells which comprise the CAR and the nucleic acid/vector) (Orentas, ¶ 0110). Regarding claims 9 and 11, Orentas teaches that the engineered immune cells or Orentas were prepared by transducing T cells with retroviral CAR expression vectors (inherently integrates into host chromosome) (Orentas, ¶ 0136).
Orentas does not teach that the extracellular binding domain of the CAR of Orentas comprises an extracellular binding domain that binds to a HSP70 and comprises SEQ ID NOs: 58-273 of instant SEQ ID NO: 1. Orentas does not teach a method of treating cancer, wherein said cancer abnormally expresses the LOX1 receptor HSP70, said method comprising administering a pharmaceutical composition comprising the engineered immune cell described in claim 10 comprising the nucleic acid described in claim 7 to a subject in need thereof.
Cao teaches on the subject of LOX1-Fc fusion protein targeting the LOX1 ligand OxLDL (Cao, Abstract). Cao teaches that LOX1 exhibits high affinity binding to its ligand, with LOX1 binding OxLDL with a KD of 1.71 * 10-8 M (Cao, p 4910, ¶ 4). Cao teaches that the extracellular LOX1-based binding domain of CAO comprises AAs 61-274 of LOX1 (entire extracellular domain) (Cao, p 4917, ¶ 4). Cao teaches that a LOX1-Fc fusion of Cao efficiently bound and blocked binding of OxLDL to cell surface LOX1 (Cao, p 4914, ¶ 2).
Kumar teaches on the subject of HSP70 as a therapeutic cancer target (Kumar, Abstract). Kumar teaches that cells do express HSP70 at basal levels under non-stressed conditions, with enhanced expression of HSP being a characteristic of cancerous cells (Kumar, p 6, ¶ 1). Kumar teaches that anti-cancer therapy elicits HSP70 expression in cancer cells, providing a protective effect and that malignant cells express more HSP70 than normal cells during tumor progression (Kumar, p 6, ¶ 1). Kumar also teaches that HSP70 is considered a tumor-selective target because it is found on the surface of tumor cells but not normal cells (Kumar, p 10, ¶ 2). Kumar teaches that LOX1 is one of the receptors for tumor-derived HSP70 (Kumar, p 9, ¶ 2).
It would be prima facie obvious to one of ordinary skill in the art to substitute the CD276 binding domain of the CAR of Orentas with the LOX1 extracellular binding domain of Cao, wherein said LOX1 binding domain binds HSP70 and administer engineered immune cells comprising such a LOX1-derived CAR and also comprising nucleic acids encoding such a LOX1-derived CAR in methods of treating HSP70 aberrant expressing cancer in view of the teachings of Kumar. The net result of this substitution would be a CAR comprising an extracellular binding domain comprising the extracellular LOX1 binding domain of Cao (same as AAs 61-273 of SEQ ID NO: 1), which binds HSP70, and the transmembrane and the intracellular domains of Orentas as well as a method of treating HSP70 aberrant expressing cancers, said method comprising administering pharmaceutical compositions comprising engineered immune cells comprising such a LOX1-derived CAR as well as nucleic acids encoding such a LOX-1 derived CAR. One of ordinary skill in the art would be motivated to do this in order to better treat cancers that express aberrant HSP70. One of ordinary skill in the art would have a reasonable expectation of success substituting the CD276 binding domain of the CAR of Orentas with the LOX1 extracellular binding domain of Cao, wherein said LOX1 binding domain binds HSP70 and administer engineered immune cells comprising such a LOX1-derived CAR as well as nucleic acids encoding such a LOX1-derived CAR in methods of treating HSP70 aberrant expressing cancer in view of the teachings of Kumar because: 1) Orentas teaches engineered host T cells transduced to anti-CD276 CARs of Orentas, which comprise the transmembrane and extracellular sequences of SEQ ID NO: 8, are administered methods of CD276-expressing cancers, 2) Kumar teaches that HSP70 is highly expressed on cancer cells compared to healthy cells, making HSP70 also a target molecule for cancer, 3) Kumar teaches that LOX1 is a ligand for HSP70, 4) Cao teaches that LOX1 has a high affinity for its ligands and that LOX1 fusion proteins used as a means to target LOX1 ligands before the effective filing date of the instant application and 5) one of ordinary skill in the art would reasonably deduce from the teachings of Cao and Kumar that the LOX1 extracellular binding domain of Cao would make an effective binding agent targeting cancer-associated HSP70 and 6) one of ordinary skill in the art would reasonably deduce that, since Orentas teaches T cells expressing a CAR comprising a CD276 targeting domain are used in methods of treating CD276-expressing cancer that T cells expressing an HSP70-targeting CAR would be capable of use in methods of treating HSP70-expressing cancer.
It would be prima facie obvious to one of ordinary skill in the art to start with the LOX1 binding domain taught by Cao comprising AAs 61-273 of instant SEQ ID NO: 1 and arrive at the instant claimed LOX1 binding domain comprising AAs 58-273 of instant SEQ ID NO: 1 via routine experimentation. One of ordinary skill of the art would be motivated to do this in order to optimize the LOX1 binding domain of Cao for fusion to a sequence having a transmembrane domain by including at least some of the transmembrane domain of LOX1. One of ordinary skill in the art would have a reasonable expectation of success to starting with the LOX1 binding domain taught by Cao comprising AAs 61-273 of instant SEQ ID NO: 1 and arriving at the instant claimed LOX1 binding domain comprising AAs 58-273 of instant SEQ ID NO: 1 via routine experimentation because the two sequences are very close in length and routine experimentation is within the purview of one of skill in the art.
Additionally, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.) (See MPEP 2144.05(I)).
Additionally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (See MPEP 2144.05(II)(A)).
Conclusion
Claims 1-18 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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