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
1. Applicant’s response filed 6/7/23 and Applicant’s amendment and response filed 2/16/26 are acknowledged and have been entered.
2. Applicant's election without traverse of Group I and species of CAR and phospholipid ether in Applicant’s amendment and response filed 2/16/26 is acknowledged.
Claims 1-3, 5-14 and 20-23 read on the elected species. Upon consideration of the prior art, examination has been extended to the species recited in claim 4, the species of TCR, and the other recited species in the claims.
Claims 1-14 and 20-23 are presently being examined. Claims 1 and 13 are independent claims.
3. The use of the terms FLAG-TAG and STREP-TAG, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
4. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
5. 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.
6. Claims 1-14 and 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Applicant has broadly claimed a complex comprising a chimeric antigen receptor (CAR) or a TCR; and a compound comprising a lipid, wherein the lipid comprises a hydrophobic group, a polar head group, and a target moiety, wherein the CAR or TCR is specifically bound to the target moiety, and wherein the target moiety is selected from: one of the Markush alternatives recited in instant claim 8, a target moiety comprising/comprises fluorescein or a derivative thereof (claim 9, claim 21, and claim 23), the structure recited in claim 12 that comprises fluorescein (see Figure 1A of the instant specification), or claims 1-14 and 20-23 that recite a TCR that specifically binds to a target antigen.
The specification does not disclose a representative number of species of such CAR or TCR (i.e., the sequences for the CARs or TCRs that must possess the functional property of specifically binding to the recited target moiety) in the claimed complex that specifically binds to the recited target moieties, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function. There is no evidence of record for a representative number of species with binding specificity to the recited target moieties.
In addition, the genus of such recited target moieties is structurally diverse, as is the ligands that bind them. Even if this were not so, there is no structure/function relationship even for binding of a CAR (commonly comprised of antigen-binding antibody fragments as an extracellular domain) or a TCR to a same targeting moiety (i.e., to a same antigen).
The specification discloses that “target moiety has its plan and ordinary meaning when read in light of the specification and may include but is not limited to for example, a specific group or site on a molecule or chemical that is a binding target for another chemical or protein of interest ([0039]). The specification discloses that in some alternatives, the target moiety is a hapten, poly-(His) tag, STREP-TAG, FLAG-TAG, V5-tag, Myc-tag, HA-tag, NE-tag, biotin, digoxigenin, DNP or fluorescein ([0006]) or GFP, YFP, OFP, RFT FRFP, or FITC ([0034]). The specification discloses a laundry list of potential target moieties, for instance in the disclosure spanning page 2 through the first half of page 23 (all are chemical moieties), last four lines on page 224 [0031]).
The specification discloses that a “TCR” has its plain and ordinary meaning when read in light of the specification, and may include but is not limited to, for example, a molecule that is found on the surface of T cells that is responsible for the recognition of fragments of antigen (peptide) bound to a MHC molecule ([0038]).
The specification discloses that chimeric antigen receptors or “CARs” are synthetic receptors that include an extracellular ligand binding domain, most commonly a scFv linked to intracellular signaling components ([0003]). The specification discloses that screening a variety of different CAR structures can be performed by contacting cells comprising CARs which are specific for a target moiety with a substrate or binding agent comprising said target moiety and evaluating the binding of the CARs to the substrate or binding agent, wherein the CAR comprises an antibody or antibody fragment, scFv or a protein or portion thereof that is designed to recognize the target moiety. The specification discloses that designing proteins for interactions are known to those skilled in the art, and are desirable very specific, as proteins can interact with a large number of proteins or chemicals such as FL (fluorescein), for example, thus successful design should utilize selective binders ([0090]).
The specification disclose synthesizing a target moiety that is termed FL-PLE (fluorescein-phospholipid ether) that comprises fluorescein as the target moiety (e.g., [0094], [0095], Figure 1A of the specification). The specification discloses a T cell comprising a CAR specific for fluorescein, but does not disclose the amino acid sequence of the fluorescein binding region (e.g., [0099]).
One of skill in the art was aware that the number and sequence of antibodies that bind to a single protein or antigen is a very large and structurally diverse genus; that is, there is no common structural relationship even for antibodies that bind to a same antigen, epitope thereof, or overlapping epitopes thereof. As pertains to lack of a structure/function relationship, the following evidentiary references teach the large structural diversity inherent in different antibodies that bind to a same epitope or to overlapping epitopes of an antigen.
Evidentiary reference Poosarla et al. (Biotechn. Bioeng., 2017, 114(6): 1331-1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes…in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Evidentiary reference Khan and Salunke (J. Immunol, 2014, 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity…Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naïve BCR repertoire, because Kaji et al….have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Evidentiary reference Lloyd et al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Evidentiary reference Edwards et al. (JMB, 2003, 334: 103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lamda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Evidentiary reference Biorad (2016, 6 pages) teaches that TCRs bind to peptide antigen/MHC class I or class II complexes, with the main interaction being with CDRs of the TCRs with a peptide/MHC complex. TCR diversity is equally diverse when considering binding to its cognate MHC/peptide complex. The genus of peptide/MHC complexes is also very large and structurally diverse (over 35,000 different human MHC molecules alone and peptides from potentially any in the universe of proteins of artificial and natural repertoires) (see evidentiary reference HLA Nomenclature, 2023, 2 pages). Nor is there a structure/function relationship for the amino acid sequence(s) of the CDRs of a TCR (that provide most of the binding interaction) and binding to a particular peptide/MHC complex, as the skilled artisan was aware that structurally diverse TCRs bind to a same pMHC
complex, as is evidenced for example, by evidentiary reference Singh et al. (J. Immunol. 2017, 199: 2203-2213):
Binding specificity arises from the structural and physicochemical “fit” between a receptor and its ligand; however, the concept of structural fit is elusive and not easily quantified from structures. Structural environments impact interatomic interactions, both attractive and repulsive. Some interactions operate at long ranges, outside of what might traditionally be viewed as a receptor-ligand interface. Motion, which can strongly influence how two molecules interact, is poorly gauged from structures. Structures themselves are the results of experiments with noise and error. (See paragraph spanning columns 1-2 on page 2203.)
The binding specificity of the TCR is one of the key factors that contribute to specificity in T cell-mediated immunity. Structural and biochemical investigations have profoundly influenced our understanding of the determinants of TCR specificity. A key finding is the inability to ascribe specificity [of binding] to TCR hypervariable loops or the peptide alone: rather the composite pMHC surface and the juxtaposition of various loops of the TCR force us to consider the interface in its entirety. This includes examining the connectedness between the various components, such as peptide and MHC or hypervariable and germline loops. (See first paragraph of Conclusions section.)
Adequate written description is not provided by describing an antigen to which an antibody (in a CAR) or a TCR binds (see Amgen Inc. v. Sanofi, 598 U.S. 594 (2023)).
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the CAR and TCR of the complex recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such CARs and TCRs and hence not in possession of the claimed complex at the time the instant application was filed.
Applicant is also reminded that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (Ariad Phar., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011).
7. Claims 1-14 and 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
“To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S, 108F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997) (quoting In re Wright, 999F2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)). In In re Wands 8 USPQ2d 1400 (CAFC 1988), a number of factors are set forth which a court may consider in determining whether a disclosure would require undue experimentation. These factors were set forth as follows: (1) the quantity of experimentation necessary, (2) the amount of 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. All the factors need not be reviewed when determining whether a disclosure is enabling. Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927F2.d 1200, 1213, 18 USPQ2d 1016, 1027 (Fed. Cir. 1991) (noting that the Wands factors “are illustrative, not mandatory. What is relevant depends upon the facts.”).
Claim interpretation: The complex of claims 1-12 and 20-23 comprises a CAR or a TCR, either one expressed on a cell or naked (i.e., not cell expressed and not comprising any effector regions or moieties), and the CAR or TCR is specifically bound to a target moiety on the compound comprising a lipid that comprises a hydrophobic group, a polar head group, and a target moiety. The cell of claims 13 and 14 can either be a cell having a CAR or a TCR expressed on its surface and specifically bound to the lipid through the target moiety on the lipid, or it can be a cell that has the lipid intercalated in a lipid bilayer of the cell and wherein a naked CAR or a naked TCR is specifically bound to the lipid through the target moiety on the lipid. The open transitional phrase “comprising” recited in instant base claim 1 opens the claims to encompass other non-recited components.
The specification does not disclose how to make and/or use the instant invention:
(1) a complex comprising a CAR or a TCR, and a compound comprising a lipid, wherein the lipid comprises a hydrophobic group, a polar head group, and a target moiety, wherein the CAR or TCR is specifically bound to the target moiety, and including the limitations recited in the dependent claims, and (2) cell comprising the complex of claim 1, wherein the CAR or TCR is expressed on the surface of the cell, or the lipid is intercalated in a lipid bilayer of the cell, and including wherein the cell is one of the types recited in dependent claim 14.
The specification has not enabled the breadth of the claimed invention because the claims encompass: (1) using a complex comprising a cell expressed CAR or a TCR that is already bound to a target moiety of the recited lipid, wherein it is unpredictable that prebinding the CAR or TCR to the lipid and potentially activating the cell through virtue of that binding results in a complex that can be used for the purpose disclosed in the specification for the individual components thereof when administered separately (claims 1-12, 20-23 and claims 13 and 14 in part as pertains to the first recited alternative), (2) using a complex comprising a naked CAR or naked TCR (that are polypeptides and are not cell expressed) bound to the lipid that is a free lipid (not in a cell), wherein it is unpredictable that the complex can be used, as the CAR or TCR do not have effector functionality (the free lipid by itself is expected to intercalate into a cell membrane in vivo, however the lipid is not expected to have signaling functionality in the cell into which it is intercalated) (claims 1-12, 20-23, and the second alternative recited in claims 13 and 14), and (3) it is unpredictable that a CAR polypeptide can be made at all due to the very hydrophobic nature of the transmembrane domain thereof.
The state of the art is such that it is unpredictable in the absence of appropriate evidence whether the claimed compositions can be made and/or used for their disclosed purpose.
The disclosed purpose of the individual components of the claimed complex is to target a cancer in a subject to treat, ameliorate or inhibit a cancer ([0087], [0006], [0011]) through activation of the cell by virtue of specific binding of the CAR expressed on a cell (that is administered separately from the lipid) to the target moiety on the lipid that is intercalated into the membrane of a tumor cell after administration of the lipid. The specification discloses that the composition that comprises the lipid which in turn comprises a targeting moiety is to be administered to a subject and administering a cell comprising a CAR or TCR which is specific for the target moiety separately from the lipid (e.g., [0076], [0087], [0004]).
The specification discloses one working example wherein U87 cells (i.e., cells of a human glioblastoma tumor cell line) harboring fluorescent markers were incubated with FL-PLE (i.e., fluorescein (target moiety)-phospholipid ether) overnight in vitro. The cells were then mixed with anti-FL-CAR CD8+ T cells (resulting in tumor cells having the lipid intercalated into their cell membranes and specifically bound to the T cells through binding of the CAR antibody fragment to the fluorescein target moiety on the lipid) and injected into the brain of a mouse (i.e., both tumor cells and T cells bound together were injected). The anti-FL CAR T cells were able to activate and slow down engraftment of the tumor U87 cells to which they are attached. However, the specification discloses that “This demonstrates that the FL-PLE works as a target for CAR T-cell recognition in a living model”, not as a working example of how the complex comprising both the anti-target-CAR T cell and the target moiety-comprised lipid is to be used (e.g., [0022]). Likewise, the specification does not disclose any working examples of using a complex comprising a naked anti-target moiety TCR prebound to a target moiety comprised lipid (i.e., the naked TCR cannot signal, e.g., unlike that disclosed at paragraph [0021] of the specification, nor does it comprise any effector portion). Also, the specification does not disclose how to use a cell having a lipid intercalated into its lipid bilayer and bound to a naked TCR or a CAR polypeptide (neither disposed on a cell).
The specification discloses that “target moiety has its plan and ordinary meaning when read in light of the specification and may include but is not limited to for example, a specific group or site on a molecule or chemical that is a binding target for another chemical or protein of interest ([0039]). The specification discloses that in some alternatives, the target moiety is a hapten, poly-(His) tag, STREP-TAG, FLAG-TAG, V5-tag, Myc-tag, HA-tag, NE-tag, biotin, digoxigenin, DNP or fluorescein ([0006]) or GFP, YFP, OFP, RFT FRFP, or FITC ([0034]). The specification discloses a laundry list of potential target moieties, for instance in the disclosure spanning page 2 through the first half of page 23 (all are chemical moieties), last four lines on page 224 [0031]).
The specification discloses a laundry list of lipids and components thereof that may be used (e.g., [0005]).
The specification discloses that a “TCR” has its plain and ordinary meaning when read in light of the specification, and may include but is not limited to, for example, a molecule that is found on the surface of T cells that is responsible for the recognition of fragments of antigen (peptide) bound to a MHC molecule ([0038]).
The specification discloses that chimeric antigen receptors or “CARs” are synthetic receptors that include an extracellular ligand binding domain, most commonly a scFv linked to intracellular signaling components ([0003]). The specification discloses that screening a variety of different CAR structures can be performed by contacting cells comprising CARs which are specific for a target moiety with a substrate or binding agent comprising said target moiety and evaluating the binding of the CARs to the substrate or binding agent, wherein the CAR comprises an antibody or antibody fragment, scFv or a protein or portion thereof that is designed to recognize the target moiety. The specification discloses that designing proteins for interactions are known to those skilled in the art, and are desirable very specific, as proteins can interact with a large number of proteins or chemicals such as FL (fluorescein), for example, thus successful design should utilize selective binders ([0090]).
Evidentiary reference Lu et al. (Front. Oncol. 2019, 9, article 151, pages 1-20) which counts the instant inventors amongst its authors teaches a tumor-targeting ligand linked to a chemical target antigen for a chimeric antigen receptor (CAR) T cell that is FL (i.e., fluorescein or FITC), linked to folic acid, a tumor-targeting ligand. Lu et al. teach that the folate-linker-FL is administered separately from the CAR-T cells that are specific for the target moiety FL in a variety of cancer patients having folate receptor positive tumors (see the entire reference) (that is, the folate binds to a folate receptor on a folate-receptor positive tumor cell, then the CAR-T cells that are specific for FL are administered that bind the FL portion of the folate-linker-FL construct that is attached to the folate receptor on the tumor cell). Although the folate portion of the tumor-targeting- and-FL-comprising molecule is not meant to incorporate into a cell membrane, but rather to bind to a cognate folate receptor on a tumor cell, the principle is similar, wherein the tumor-targeting molecule must be attached to the tumor cell, then when attached, contacted with the CAR-T cell, wherein binding of the CAR-T cell with the CAR target comprised in the molecule activates the T cell through the intracellular signaling portion of the CAR.
There is no evidence of record that a complex of a CAR-T cell or any other CAR-cell that is activated by virtue of the CAR binding to its ligand on the lipid compound (i.e., a complex of a CAR-T cell or other cell with the lipid molecule that comprises the target moiety of the CAR and the portion that attaches to a target cell such as a tumor cell) rather than being activated when it is bridged to a tumor target cell that has intercalated the lipid compound before the CAR-cell is contacted with the lipid compound in complex with the recited compound comprising a lipid can be used for its disclosed purpose in treating a cancer. There is also no evidence of record that a naked TCR in complex with the recited lipid molecule comprising portions for attaching to a target cell and a portion that comprises the target moiety for the TCR can be used for its disclosed purpose. In addition, with regard to making and using a CAR polypeptide that is not disposed on a cell, it is unpredictable that the said polypeptide can be made and/or used due to the very hydrophobic nature of the transmembrane region (TM) of a CAR.
Evidentiary reference Hu et al (Protein Science, 2007, 16: 2153-2165) teaches that transmembrane domains have a highly hydrophobic amino acid composition and because of the near absence of water in the transmembrane environment, the whole balance of molecular interactions that stabilizes protein structure is altered (paragraph spanning pages 2153-2154, first paragraph of the Discussion section). Hu et al teach that proteins and their domains are significantly influenced by their environment, and the expression, purification, and sample preparation for these constructs can be challenging (first paragraph on page 2153). See entire reference.
There is insufficient guidance in the specification as to how to make and/or use instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
8. 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.
9. Claims 8-11 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.
a) Claim 8 contains the trademark/trade names FLAG-TAG and STREP-TAG. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe tags and, accordingly, the identification/description is indefinite.
b) Claim 10 is indefinite in the recitation of “a hapten (2x)” because it is not clear what is meant, if this means two instances of a same hapten or if it is a particular hapten.
10. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
11. Claims 9 and 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
a) Claim 9 recites the limitation “wherein the target moiety is selected from the group consisting of ….a fluorescein, and a derivative thereof” by virtue of its dependence on claim 8, and it also recites “wherein the target moiety comprises a fluorescein or a derivative thereof” which is a broader recitation due to the limitation “comprises”. The said recitation broadens the claim rather than further limiting it.
b) Claim 22 recites “The complex of claim 20, wherein the lipid further comprises a spacer between the target moiety and the polar head group”. However, the structure recited in claim 20 already has a PEG spacer between the target moiety and the polar head group (see Figure 1A wherein section “ii” is the PEG spacer, section “iii” is the polar head group, and section “i” is the target moiety. The target moiety in claim 20 is represented by “R”. The PEG spacer in the compound recited in claim 20 is narrower than the broader “spacer” recited in claim 22. The said recitation broadens the claim rather than further limiting it.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
12. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 16/965,859 case that issued as US 12,312,416 as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claim interpretation: The complex of claims 1-12 and 20-23 comprises a CAR or a TCR, either one expressed on a cell or naked, and the CAR or TCR is specifically bound to a target moiety on the compound comprising a lipid that comprises a hydrophobic group, a polar head group, and a target moiety. The cell of claims 13 and 14 can either be a cell having a CAR or a TCR expressed on its surface and specifically bound to the lipid through the target moiety on the lipid, OR it can be a cell that has the lipid intercalated in a lipid bilayer of the cell and wherein a naked CAR or a naked TCR is specifically bound to the lipid through the target moiety on the lipid. The open transitional phrase “comprising” recited in instant base claim 1 opens the claims to encompass other non-recited components.
Claims 1, 5, 6, 8, 9, 13, 14 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,312,416.
The claims of US 12,312,416 are drawn to a method of treating or inhibiting a solid tumor in a subject in need thereof, wherein the subject’s bloodstream comprises engineered T cells comprising a CAR that specifically binds fluorescein, the method comprising administering a composition comprising fluorescein conjugated to a phospholipid ether in an amount effective to label tumor cells in the solid tumor, wherein the CAR-T cells specifically binds the fluorescein and kill tumor cells (claims 1-17 of ‘416) or are drawn to a method of treating or inhibiting a solid tumor in a subject in need thereof comprising administering to the subject a composition comprising fluorescein conjugated to a phospholipid ether (FL-PLE) in an amount effective to label tumor cells in the solid tumor, and a CAR-T cell, wherein the CAR specifically binds the fluorescein (claim 18 of ‘416).
Although the claims at issue are not identical, they are not patentably distinct from each other because one of skill in the art was aware that phospholipid ethers consist of a polar head group and one or more hydrophobic tails, with the hydrophobic tail being linked via an ether bond, the CAR-T cell and the FL-PLE form a complex in vivo, the method of the claims of ‘416 form the complex in vivo, and the claims of ‘416 anticipate the instantly claimed complex because they recite the individual components and the binding specificity of the individual components to each other. In addition, the instant claims do not recite that the complex or the cell comprising the complex is isolated. The claims of ‘416 that recite a masking moiety (claims 3-5 of ‘416) are included in this rejection because claim 4 of ‘416 recites “wherein the masking moiety is cleaved by reactive oxygen species (ROS) present in a tumor microenvironment of the solid tumor” and therefore, the masking moiety is not part of the complex.
13. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 17/758,959 case that issued as US 12,570,716 as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claim interpretation: The complex of claims 1-12 and 20-23 comprises a CAR or a TCR, either one expressed on a cell or naked, and the CAR or TCR is specifically bound to a target moiety on the compound comprising a lipid that comprises a hydrophobic group, a polar head group, and a target moiety. The cell of claims 13 and 14 can either be a cell having a CAR or a TCR expressed on its surface and specifically bound to the lipid through the target moiety on the lipid, OR it can be a cell that has the lipid intercalated in a lipid bilayer of the cell and wherein a naked CAR or a naked TCR is specifically bound to the lipid through the target moiety on the lipid. The open transitional phrase “comprising” recited in instant base claim 1 opens the claims to encompass other non-recited components.
Claims 1, 5, 6, 8, 10, 13, 14, 20 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,570,716.
The claims of US 12,570,716 are drawn to a CAR or to a system comprising an effector cell comprising the CAR and further comprising a composition comprising a DNP moiety that the CAR specifically binds to, wherein the DNP moiety is attached to a lipid such as a phospholipid ether that is integrated into a target cell surface, such as a cancer cell, wherein the DNP (dinitrophenol) moiety is joined to the PLE by a PEG spacer, and wherein the lipid structure is identical to that recited in instant claim 20 (“R” is the target moiety in instant claim 20, whereas DNP is the target moiety in the claims of US 12,570,716).
Although the claims at issue are not identical, they are not patentably distinct from each other because one of skill in the art was aware that phospholipid ethers consist of a polar head group and one or more hydrophobic tails, with the hydrophobic tail being linked via an ether bond to the polar head group (the specification of ‘716 at [0079] also discloses that a PLE is a lipid in which one or more of the carbon atoms on a polar head group are bonded to an alkyl chain via an ether linkage) and the specification of ‘716 does not disclose a limiting definition for the limitation “system”. The anti-DNP-CAR-effector cell and the DNP-PLE of the claims of ‘716 form a complex, and the number of alkyl carbons constitutes routine optimization that was within the purview of one of ordinary skill in the art to determine.
14. Court rulings have been quite clear that ONLY DIVISIONAL applications are entitled to the shield from double patenting under 35 USC 121. Indeed, in AMGEN INC v. HOFFMANN LA ROCHE LTD GMBH LA (Nos. 2009-1020, 2009-1096) the court discusses this issue at length and states:
Turning to the legislative history, the court observed that a House Report also referred specifically to “divisional application[s].” Id. Notably absent from the legislative history, in the court's view, was a suggestion “that the safe-harbor provision was, or needed to be, directed at anything but divisional applications.” Id. at 1361. From there, the court “conclude^] that the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications.” Id. at 1362. Accordingly, the court decided that the § 121 safe harbor did not apply to the patent before it, which issued from a continuation-in-part application. Id.
We are persuaded by the reasoning in Pfizer that the § 121 safe harbor provision does not protect continuation applications or patents descending from only continuation applications. The statute on its face applies only to divisional applications, and a continuation application, like a continuation-in-part application, is not a divisional application.
Given that Applicant chose to file the 17/265,484 case as a separate unrelated application, not as a DIV of the instant application, the instant rejection has been set forth.
Claims 1, 3, 5, 6, 8-14 and 20-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 115-122, 124, 128, 133-135, 137-141 and 143-147 of copending Application No. 17/265,484.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because the specification of 17/265,484 does not disclose a limiting definition for the limitation “system”, and because the instant claims recite the open transitional phrase “comprising”, opening the complex and cell recited in the instant claims to encompass other non-recited elements.
Claims 115-121, 128, 133-135, 137, 140 and 143-146 of ‘484 are drawn to a system comprising an effector cell comprising a first and second CAR, wherein the first CAR is specific for a tumor antigen and the second CAR is specific for a hapten and further comprising a hapten-APC, wherein the hapten-APC comprises the hapten which may be one of fluorescein, urushiol, quinone, biotin and DNP or a derivative thereof, wherein the hapten is covalently attached to a phospholipid integrated into the plasma membrane of the hapten-APC, and wherein the second CAR of the effector cell is capable of directly binding the hapten of the hapten-APC. The effector cell may be a T cell, including a CD8+ cytotoxic lymphocyte selected from a CD8+ T cell, central memory effector, effector memory, or bulk T cell, or including a CD4+ cytotoxic lymphocyte selected from a CD4+ T cell, central memory effector, effector memory, or bulk T cell, or including a precursor T cell or a hematopoietic stem cell. The phospholipid may be PDE (a phospholipid ether) or a DHPE. The phospholipid is linked to the happen via a PEG spacer of a length of 1 to 16 PEG subunits, and wherein the hapten attached to the phospholipid of claim 145 of ‘484 has a structure that is a species of the structure recited in instant dependent claim 12 (the target moiety is fluorescein, the PEG is 1-16 subunits, and the alkyl group is C2-18).
Claims 122, 124, 138, 139 and 147 of ‘484 are drawn to a method of treating, inhibiting, or ameliorating a cancer in a subject comprising administering the effector cell and the hapten-APC, including wherein prior to administering the effector cell, the method further comprises stimulating the effector cell by contacting the effector cell with the hapten-APC in vitro (i.e., a complex comprising the CAR-effector cell bound to the hapten on the APC). The hapten may be one of fluorescein, urushiol, quinone, biotin DNP, or a derivative thereof, and the happen may be covalently linked to the phospholipid via a PEG spacer of length 1-16 PEG subunits, and wherein the phospholipid is integrated into the plasma membrane of the hapten-APC.
Claims 141 and 143 of ‘484 are drawn to an in vitro or ex vivo method of stimulating a CAR-T cell comprising contacting the CAR-T cell with the hapten-APC.
Although the claims at issue are not identical, they are not patentably distinct from each other because
15. No claim is allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights