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 .
Application Status
Claims 1, 4, 6, 10-11, 15, 17, 19, 21-22, 25-26, 28, 45-46, 48, 51-52, 55 and 57 are pending and examined on the merits herein.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4, 10, 15, and 17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claims 1, 4, 10, 15, and 17 are directed to a natural phenomenon because the claims recite a product of nature (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is:
Claims 1, 4, 10, 15 – a modified CD117 polypeptide comprising one or more amino acid modifications as compared to WT CD117; and
Claim 17 – a nucleic acid molecule that encodes for an isolated peptide as recited in claim 29.
Claims 1, 4, 10, 15 and 17 are directed to a natural phenomenon because the claims recite a natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: the modified CD117 polypeptide as recited in claim 1.
The instant specification does not teach the definition of the term “modified”. The instant specification further teaches that CD117 includes an approximately 519 amino acid extracellular domain comprised of five immunoglobulin-like domains, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues wherein approximately 184 amino acids of the extracellular domain are surface exposed, which were identified based on x-ray crystallographic studies (para 0064).
Prior art teaches naturally occurring modified CD117 as seen in Foster ( Biomedicines. 2018; 6(1):31; PTO-892). Foster teaches that CD117 is highly conserved and a known splice variant has higher affinity for SCF (section 2.1). Foster further teaches common oncogenic mutations in CD117 which over activate the signaling pathway upregulating proliferation, cel survival, migration and differentiation which are shown to occur in the tyrosine kinase domain and the juxta domain region but that there are also less common mutations that occur in the extracellular domain through point mutation, fame deletions or internal tandem repeats (Section 2.2).
There are no recited active steps of the claims to impose a meaningful limit on the scope of the claims. The claims of the compositions identified in the specification to contain products of nature in the human body wherein the modified CD117 polypeptide are verified. Thus, the modified CD117 polypeptides are encoded by DNA by cells and wherein the polypeptides are produced by human cells. Thus, there is no change in functional activity of the compositions.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
No additional elements are present outside of the naturally occurring product of nature present in a human (“Step 2B”) in: 1) claims 1, 4, 10, and 15 – a modified CD117 polypeptide comprising one or more amino acid modifications as compared to WT CD117; 2) claim 17 – a nucleic acid molecule that encodes for the polypeptide.
Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims contain subject matter of a natural product and do not amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 112(b)
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 4, 19, 25, 48, and 55 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 claim 4, the claim recites that the amino acid modifications do not substantially inhibit or reduce CD117 signaling, the recitation of the word substantially is subjective and therefore renders the claim as indefinite. The instant specification discloses that: As used herein, the term "substantially" means by a significant or large amount or degree. For example, to "substantially" increase may mean to increase by at least two-fold, at least three- fold, at least four-fold, at least five-fold, or at least ten-fold, and to "substantially" decrease may mean to decrease by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% (para 0061). Without a clear and concise definition of the term substantially as used in the claim the limitations of the claim are indefinite as being subject to interpretation.
Regarding claims 19, 25, and 48, the phrase "optionally" used as exemplary language as it used not as an alternative limitation but in the format of: genus, optionally species. Therefore, the species following the term “optionally” are examples of the members of the genus. This is exemplary language and renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 55, the phrase "optionally" before step ii, makes that limitation not required but then step iii is meant to follow step ii, so is step iii also optional on the condition that step ii has been performed so that the claim only requires step i?
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 6 and 11 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.
Regarding instant claim 6, the claim recites wherein the anti-CD117 antibody comprises at least five, optionally six CDRs present in any one of JSP191, AB85, CDX-0159, or FSI-174. Regarding instant claim 6, an antibody is claimed by partial structure.
Regarding instant claim 11, the claim recites one or more amino acid modifications that disrupt binding of the CD117 antibody to an epitope present in the WT CD117. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed epitope.
Summary of the teachings of the specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification demonstrates alanine scanning mutagenesis of CD117 and binding of JSP191 Fab, AB85 Fab and 104D2 (Fig 2) as well critical residues for binding from crystal structures of JSP191 Fab and AB85 Fab (Fig 3 & 4). The instant specification further teaches a table of DNA template sequences used to produce CD117 mRNAs (Fig 6), this table includes a list of 5 nucleic acid sequences. These sequences were further tested for expression, effect on antibody binding, and effect on cell growth (Figs 7-14).
There is no disclosure of antibodies comprised of less than the 6 CDRs of the recited antibody clones. There is also no crystal structure or critical residue information disclosed for CDX-0159 or FSI-174
The specification does not teach a structure activity relationship that would allow CDR residues to be determined that exhibit specificity with the WT CD117 but not the modified CD117 polypeptide for CDX-0159 or FSI-174 or any clone recited comprised of at least 5 CDRs.
Accordingly, the skilled artisan would not be able to discern a structure/function correlation for the antibody to the claimed polypeptides other than those comprising all six CDRs.
Given the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
State of the Relevant Art
Regarding Partial Structure:
Examples of antigen binding domains comprising only a VH (or less commonly, a VL) that in turn comprise only three CDRs certainly do exist in the literature, but those antibodies generally comprise unique structures such as CDR1 and CDR3’s that are elongated in length and that are often disulfide linked such as in heavy chain antibodies (De Genst et al., Developmental and Comparative Immunology, 2006, 30:187-98; entire document, specifically note “1. Introduction” and figure 1 in particular). Further, specific autonomous VH domains that can bind to antigens have also been described in the arts. Ward et al. (Nature, 1989, 341:544-546) teaches that the complete VH domains of several antibodies maintained the ability, although with reduced affinity than the VH-VL, to bind to lysozyme even when they are not paired with the corresponding VL domains (page 545, left column, 2nd complete paragraph; Table 1). Ward et al. also teaches that the autonomous VH domain lacks the binding cavity which is formed when paired with the VL domain (page 546, left column, lines 4-6). Ward et al. further teaches that the VH domain alone is very sticky and contributes to non-specific binding (page 546, left column, last paragraph). Barthelemy et al. (Journal of Biological Chemistry, 2008, 283:3639-3654) analyzed numerus autonomous VH domains that are isolated from a phage display screen that are conducive for producing single domain VH antibodies. Barthelemy et al. showed that several changes in the key residues in the VH framework region that mediates binding with the VL domain are required for stabilization of the autonomous VH domain antibodies (abstract; figure 1A and table 1). These findings further illustrates that residues in the VH framework region are required to stabilize a VH domain to form a functional antigen binding pocket and only some VH domains can function alone to bind to antigens. Furthermore, due to their increase in nonspecific binding, autonomous VH domains have not been shown to be functional in vivo to treat diseases.
Crystallization analysis of different antibody structures when unbound and bound to an antigen shows that the antigen binding domain adapts different confirmations when bound to an antigen (Choi et al., 2011, Molecular BioSystems, 2011, 7:3327-334; specifically page 3327, 1st and 2nd paragraphs in particular). Furthermore, the HV-CDR3 domain is highly variable (Choi et al., page 3327, right column, 1st full paragraph). Although greatly improved, a definitive computational method to accurately predict the structure of the antigen binding site when only analyzing just the CDR3 sequence or an “equivalent therefore” remains to be established (Choi et al., see “abstract”). Thus, a disclosure of a single CDR sequence is not sufficient to determine the antigen binding domain of an antibody because the other CDR sequences provide structure to the antigen binding domain.
Screening phage display libraries comprising human scFv have been used to isolate human antibodies that bind to a specific antigen. Griffiths et al. (The EMBO Journal, 1993, 12:725-734) teaches screening a phage display library with 2.9X107 clones of human scFv to identify the scFv for binding to different antigens (entire document, specifically page 732, see “Selection of phage library” and “screening and sequencing of clones”). One scFv is isolated to bind to MUC1, one scFv is isolated to bind to CEA, and seven different scFVs are isolated from the library to bind to TNFα (entire document, specifically note Table on page 726). This highlights one cannot simply predict which of the scFv out of the 2.9X107 scFv clones would bind to the specific antigen. Also, the phage library that is used for the screen can generate different antibodies.
Guide phage display screening of phages expressing 1.8X108 human scFv clones has been used to identity the five human CDR sequences that function with a heavy chain CDR3 sequence (Klimka et al., British Journal of Cancer, 2000, 83:252-260; page 252, left column). By performing multiple rounds of phage display using complex random pairing of human heavy variable domain with CDR1 and CDR2 sequences with the mouse HV-CDR3 and the light variable region (which has 3 CDR sequences, thus 4 CDR sequences are used in the screen), Klimka et al. identify the human heavy chain CDR1 and CDR2 sequences that can function with the mouse HV-CDR3 and light chain sequences. The identified heavy chain is then used to screen for a human light variable regions (entire document, page 259, left column, 1st full paragraph in particular). Only through a complex screen as taught by Klimka et al. is a skilled artisan able to randomly identify the remaining CDR sequences. Furthermore, similar to the phage display screening for antibodies described above, the CDR sequences that are identified to function with a particular HV-CDR3 sequence is dependent on the particular human antibody library that is used.
Guide phage display screening of phages expressing Fab was performed to isolate a human antibody that displayed similar binding properties as the parental antibody in Beiboer et al. (Journal of Molecular Biology, 2000, 296:833-849). In Beiboer et al, a disclosed variable heavy chain was mixed with a library of 108 light chain sequences and 2x107 light chain sequences to generate Fab libraries in, specifically page 834, see “Humanisation of the light chain”). Following 4 rounds of high stringent antigen selection, seven light chains were obtained (Table 2). The best binding light chain is then shuffled with a library of 1.2x107 human VH comprising the VH-CDR3 of the parent mouse antibody to obtain a Fab human antibody library (page 835, see “Humanisation of the heavy chain”). Following several rounds of screening, one high binding human antibody that maintains the VH-CDR3 sequence of the original parent mouse antibody is obtained that displayed similar binding properties as the parent antibody (abstract; page 835-837, bridging paragraph). Structural modeling of the parent mouse antibody with the selected human antibody showed that the selected human VL sequences are distinct from the parent mouse VL sequence and with each other demonstrating that the VH plays a dominant role in antigen binding (page 834-839, right column, bridging paragraph). Further, structural modeling further showed minimal structural conservation is observed in the CDRs of the human VH (which contains the same CDR3 sequence as the parent mouse antibody) with the parent mouse antibody (page 839, right column). Beiboer et al. highlighted that maintaining the VH-CDR3 sequence in a guide phage display is sufficient to screen for a human antibody with similar binding properties as the parent antibody (page 841, left column). The findings from Beiboer et al. highlighted that a skill artisan cannot predict the structural features of the antibody that will be obtained from a phage display screen when starting with a partial sequence. These findings showed that a skill artisan cannot predict the structural features of the antibody that will be obtained from a phage display screen when starting with a partial sequence, and cannot even predict the minimal structural feature of the antibody that will be obtained with a partial disclosed antibody CDR sequence that will have specific binding properties.
Regarding recitation of antibody defined by epitope:
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156pg 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3. Further, it is not possible to predict the amino acid sequence when an epitope is recited, because binding is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246). 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al., 3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 42–44, 60596, pg. 879).
Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Claim Analysis Summary:
Regarding instant claim 6, the applicant does not have possession of the large genus of antibodies possible to be generated from at least 5 CDRs present in any one of JSP191, AB85, CDX-0159, or FSI-174.
Regarding instant claim 11, the Applicant does not have written description of an antibody is claimed based on the epitope to which it binds without a sequence. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed epitope.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 15, 17, 19, 21-22, 25-26, 45, 48, 51, and 57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adusumilli (WO 2021/113432 A1; published 06/10/2021; PTO-892).
Regarding claims 1, 4, and 25, Adusumilli teaches a cell comprising: (a) an antigen-recognizing receptor that binds to an antigen, and (b) a mutant of c-Kit comprising an activating mutation (claim 1), wherein the activating mutation is selected from D816V, D816Y, D816H, D816F, N822K, V560G, or a combination thereof (claim 9). An activating mutation would not substantially reduce or inhibit CD117 signaling.
Regarding claims 17, 21-22, 26, and 48, Adusumilli teaches a method for producing an antigen-specific immunoresponsive cell, the method comprising introducing into a cell (a) a first nucleic acid sequence encoding an antigen recognizing receptor that binds to an antigen; and (b) a second nucleic sequence encoding a c-Kit mutant comprising an activating mutation (claim 37), wherein one or both of the first and the second nucleic acid sequences are comprised in a vector (claim 40), wherein the vector is a retroviral vector (claim 41), wherein the cell is a cell of the lymphoid lineage or a cell of the myeloid lineage (claim 23). Adusumilli teaches further teaches that non-limiting examples of cells of the lymphoid lineage include T cells, Natural Killer (NK) cells, B cells, dendritic cells, stem cells from which lymphoid cells may be differentiated (page 23, lines 15-17) and that c-Kit, known as CD117, is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types (page 20, lines 12-13).
Regarding claims 15 and 19, Adusumilli teaches wherein the human c-Kit comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1 (claim 11). SEQ ID NO: 1 has 100% sequence identity instant claimed SEQ ID NO: 1 and to the coding region of instant claimed SEQ ID NO: 5 as detailed on page 25 of the instant specification and translated on http://web.expasy.org/translate/ and also has 93.5% sequence identity to the whole of instant claimed SEQ ID NO: 5.
Regarding claim 45, Adusumilli teaches a pharmaceutical composition comprising a cell of any one of claims 1-36 and 55, and a pharmaceutically acceptable excipient (claim 56).
Regarding claims 51 and 57, Adusumilli teaches a method of treating and/or preventing a neoplasm, the method comprising administering to the subject a cell of any one of claims 1-36 and 55 or a pharmaceutical composition of any one of claims 56-59 (claim 62), wherein the tumor or neoplasm is a solid tumor (claim 64). Adusumilli further teaches an “individual” or “subject” herein is a vertebrate, such as a human or non-human animal, for example, a mammal (page 19, lines 28-29).
Claims 1, 4, 6, 10-11, 25-26, 46, 51-52, and 55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gibbs (WO 2020/112870 A1; PTO-892) as evidenced by Bankova (Blood Adv (2021) 5 (19): 3900–3912; PTO-892).
Regarding claims 1 and 25, Gibbs teaches a hematopoietic stem or progenitor cell (HSPC) genetically modified to express a receptor conferring a selective proliferation advantage on the genetically modified HSPC on introduction into a subject relative to endogenous HSPCs (claim 1), wherein the receptor is any of B2M/MHC-1, PD-L1, CD24, GAS6, CD47, c-Kit or a combination of multiple such receptors (claim 7), wherein the receptor is a mutant form, wherein the mutant has reduced binding to an antibody relative to the wildtype form of the receptor (claim 8), wherein the receptor is CD47 or c-Kit (claim 9).
Regarding claim 4, Gibbs teaches the mutation preferably does not significantly reduce binding of c-Kit to its ligand stem cell factor (para 0049).
Regarding claim 6, Gibbs teaches a number of antibodies that specifically bind human c-Kit are commercially available, including SRI, 2B8, ACK2, YB5-B8, 57A5, 104D2 (US20180214525) and further that AMG191 is a humanized form of SRI (US Patent nos. 8,436, 150, and 7,915,391) (para 0051).
As evidenced by Bankova, JSP191 is an anti-human CD117 mAb formerly identified as AMG191 (introduction, para 2).
Regarding claims 10-11, Gibbs teaches that if the ablation regime involves an antibody against c-Kit binding to an epitope X, then HSPCs can be genetically manipulated to express c-Kit with a mutation in epitope X such that the antibody does not bind or binds only to a reduced extent to the mutated c-Kit or the mutation can reduce or eliminate antibody binding allosterically (para 0049).
Regarding claims 26, 46, 51-52, 55, Gibbs teaches a method of treating a subject, comprising (a) administering an immunotherapeutic agent specifically binding to c-Kit to deplete endogenous HSPCs expressing c-Kit; and (b) administering replacement HSPCs genetically modified to express a receptor conferring a selective proliferation advantage on the genetically modified HSPCs relative to endogenous HSPCs and thereby resist depletion by the immunotherapeutic agent specifically binding to c-Kit, wherein the replacement HSPCs at least partially replace the endogenous HSPCs (claim 21), wherein the immunotherapeutic agent specifically binding to c-Kit is administered on multiple occasions before and after step (b) (claim 28), wherein the immunotherapeutic agent specifically binding to c-Kit is an antibody (claim 29), wherein the subject has a cancer (claim 34).
Claim Rejections - 35 USC § 103
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.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Gibbs (WO 2020/112870 A1; PTO-892) as applied to claims 1, 4, 6, 10-11, 25-26, 46, 51-52, and 55 above, and further in view of Ferrari (Nat Rev Genet 22, 216–234 (2021); PTO-892) and Kim (BMB Rep. 2021 Jan;54(1):59-69; PTO-892).
The teachings of Gibbs regarding claims 1, 4, 6, 10-11, 25-26, 46, 51-52, and 55 are detailed above.
Gibbs Some HSPCs are genetically modified by homologous recombination between a targeting construct and am endogenous locus. In some HSPCs the genetic modification is heterozygous. In some HSPCs, the genetic modification is homozygous (para 0008).
Gibbs does not teach wherein the modified cell expresses the modified CD117 polypeptide but not a wild type CD117 polypeptide.
Ferrari teaches that medicinal products based on autologous HSPCs corrected using lentiviral and gammaretroviral vectors have now been approved for clinical use and are an effective treatment modality for monogenic disorders of the blood system such as primary immunodeficiencies and β- thalassaemia (abstract). HSPCs could be exploited to deliver therapeutic molecules systemically or to affected tissues for the treatment of acquired diseases such as cancers, acquired immune disease, chronic infections or neurodegenerative disorders such as multiple sclerosis (page 230, col 2, para 3). Ferrari further teaches vector constructs for integration using lentivirus (Fig 4) and how these can be integrated into gene editing techniques in cells (Fig 5). Ferrari further teaches that for most HSCT applications, the reliance on alkylating agents for patient conditioning is associated with short- term and long- term toxic effects and the development of antibody- based conditioning regimens targeting molecules expressed on host haematopoietic cells such as CD117 or CD45 could result in the replacement of alkylating agents or their use in conjunction with alkylating agents to allow a reduction in alkylating agent dose (page 231, col 1, para 3).
Kim teaches that CRISPR/Cas9 can be applied to the manufacturing of fratricide-resistant CAR-T cells, which is particularly important in the treatment of T leukemias and lymphomas, to knock out the endogenous expression that corresponds to the antigen targeted by the CAR-T (page 61, col 2, para 2). Kim further teaches that CRISPR/Cas9 can be used to introduce genes of interest (page 62, col 1, para 2). Kim further teaches that CRISPR/Cas9 editing is not limited to the engineering of T cells, and can be used for disease modelling and therapeutic genome editing in non-T immune cells, such as hematopoietic stem and progenitor cells (HSPC) and B cells (page 62, col 2, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to knockout expression of the WT CD117 as taught by Ferrari and Kim to prevent fratricide in the method of treatment using cell expressing a modified CD117 protein. The ordinary artisan would have been motivated to do so because Ferrari teaches that medicinal products based on autologous HSPCs corrected using lentiviral and gammaretroviral vectors have now been approved for clinical use and are an effective treatment modality for multiple diseases. Kim teaches CRISPR/Cas9 can be used to introduce genes of interest as well as targeted knockdown of genes, in multiple cell types including HSPC. Kim further teaches the use of CRISPR to prevent fratricide of engineered cells used in adoptive cell therapy by knocking down the targeted antigen. Ferrari teaches that use of an anti-CD117 for haematopoietic cell depletion and has lower toxicity than traditional chemotherapy. The ordinary artisan has a reasonable expectation of success to use the CRISPR/ Cas system to express a modified CD117 protein while also knocking out endogenous WT CD117 expression to generate modified HPSC for engraftment. These modified cells can then be used in the method of treatment to ablate HSC by administration of the of an anti-CD117 and administration of the cells for engraftment wherein the administration periods will overlap.
Double Patenting
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.
Claims 1, 4, 6, 10, 15, 17, 25, 45-46, 48, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 8, 10, 13, 17, 23, 39-40, 43, 48, 55, and 79 of copending Application No. 18/276,325 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 25, and 45, the copending claims teach a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier, or diluent and a modified hematopoietic stem cell (HSC) or a hematopoietic stem and progenitor cell (HSPC), wherein the modified HSC or HSPC comprises a modified CD117 polypeptide, optionally wherein the modified CD117 polypeptide has constitutive c-Kit signaling and/or kinase activity, and optionally wherein the modified cell is capable of proliferation and/or survival when contacted with an anti-c-Kit monoclonal antibody capable of inhibiting proliferation and/or survival of an HSPC expressing only a wild-type CD117 (claim 1 and 17); wherein the modified CD1177 comprises one or more amino acid modifications as compared to the wild-type CD117 polypeptide (claim 8).
Regarding claim 4, the copending claims teach wherein the c-Kit signaling and/or kinase activity of the modified CD117 is not substantially inhibited by an anti-c-Kit monoclonal antibody and/or wherein the anti-c-Kit monoclonal antibody inhibits binding of SCF to CD117 (claims 2 and 39-40).
Regarding claim 6, the copending claims teach wherein the anti-c-Kit monoclonal antibody comprises one or more of the six CDRs present in any one of JSP191, AB85, CDX-0159, or FSI-174 or is JSP191, AB85, CDX-0159, or FSI-174 (claims 4 and 43).
Regarding claim 10, the copending claims teach wherein one or more of the amino acid modifications are present within surface exposed amino acid residues of the extracellular domain, within the membrane spanning domain, or within an intracellular domain of the modified CD117 polypeptide (claims 10 and 48).
Regarding claim 15, the copending claims teach wherein the modified CD117 polypeptide has at least 90%, at least 95%, at least 98%, or at least 99% sequence homology to a wild type CD 117 polypeptide (claim 13).
Regarding claim 17, the copending claims teach a nucleic acid encoding the modified CD117 polypeptide of claim 39 (claim 55).
Regarding claim 46, the copending claims teach further comprising one or more anti-CD117, anti-CD47, anti-CD40L, anti-CD122, anti-CD4, and/or anti-CD8 antibody (claim 23).
Regarding claim 48, the copending claims teach a method of modifying a cell, comprising introducing the nucleic acid into the cell, optionally wherein the cell is transiently modified, and optionally wherein the method is for preparing modified cells for hematopoietic cell transplantation (HCT) into a mammalian subject (claim 79).
Regarding claim 51, the copending claims teach a method of treating a mammalian subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 1 (claim 25).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
Prosecution Insights