DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 03/23/2023, is a 371 filing of PCT/EP2021/076324, filed 09/24/2021, and claims foreign priority to EP 20198096.8, filed 09/24/2020.
Status of Claims/Application
The preliminary amendment of 10/18/2023 is acknowledged. Claims 3-4 and 6-14 are amended; claim 15 is cancelled; and claims 16-23 are new. Accordingly, claims 1-14 and 16-23 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/30/2023 and 07/31/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The X axis of the plot in Figure 5 recites sequences that are not identified with an appropriate SEQ ID NO either in the drawing or in the description of the figure in the specification.
The abstract recites the sequence “LYVDSLFFL” in line 2 without an appropriate SEQ ID NO.
In the specification, amino acid sequences are recited in the following locations without an appropriate SEQ ID NO: Page 53: lines 10 and 20; and Page 58, line 20;
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification and Abstract Objections
The specification is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 54, line 14, recites the following hyperlink. The prefix and non-top level domain are bolded for clarity: https://www.ebi.ac.uk/ipd/imgt/hla/
Appropriate correction is required.
The abstract is objected to because it contains legal phraseology that should be avoided, such as “said TCR”, “said nucleic acid molecule”, and “said vector”. The abstract also uses implied phrases such as “The prevention invention relates to” and “The present invention further relates to”.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Interpretation
Claims 6 and 7 recite variable region sequences that include amino acid sequences that are at least 80% similar to the recited sequences which include the entire variable domain as well as portions within the variable domain which are limited using position numbers. For instance, claim 6 (Aa2) recites that the TCR alpha chain variable region comprises an amino acid sequence that is at least 80% similar to SEQ ID NO: 16; and an amino acid sequence that is 80% similar to positions 47-51 of SEQ ID NO: 16; and an amino acid sequence that is 80% similar to positions 69-75 of SEQ ID NO: 16; and an amino acid sequence that is 80% similar to positions 47-51 of SEQ ID NO: 16. Claim 6 (Ab2), (Ba2), and (Bb2), and claim 7 recite similar limitations.
In the instant office action the claims are interpreted as requiring that the variable region has at least 80% similarity to the entire sequence (as an example, SEQ ID NO: 16) and that the 80% similarity can be all in one of the recited amino acid ranges recited, or among the entire sequence, so long is there is at least 80% similarity over the entire sequence.
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.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 recites the limitations (Aa1), (Aa2), (Aa3), (Ab1), (Ab2), and (Ab3) in part (A) and (Ba1), (Ba2), (Ba3), (Bb1), (Bb2), and (Bb3) in part (B). There is insufficient antecedent basis for these limitations in the claim. The claim depends on claim 1, which only recites (Aa), (Ab), (Ba), and (Bb). Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
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.
Claim 10 is 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.
Claim 10 depends on claim 9 and ultimately on claim 1 and recites that the nucleic acid molecules encoding the TCR of claim 1 comprise a sequence with at least 80% identity to any one of the recited sequences. Claim 1 requires that the TCR comprise an amino acid sequence with at least 80% similarity to those recited.
The sequences recited in claim 10 include SEQ ID NOs: 3, 5, 7, 9, 31, 33, 35, and 37. These sequences are identified in the instant disclosure as being nucleic acid sequences that encode T116-49 and T402-93 alpha chain CDRs 1-2 and beta chain CDRs 1-2 (see table 1, pages 41-42). In the scope of claim 10 which encompasses any of these sequences alone, the claim does not include all of the limitations of the claim upon which it depends and does not further limit the claim upon which it depends as it does not require one of the CDR3 sequences recited in instant claim 1.
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.
Claim Rejections - 35 USC § 112(a)- Written Description
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 1-14 and 16-23 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.
The instant claims are drawn to a genus of TCRs claimed as being capable of binding to a polypeptide comprising an amino acid sequence of SEQ ID NO: 2, where not more than 4 amino acids have been substituted or to a portion of said polypeptide, or to the respective HLA-A bound form of said polypeptide or portion thereof.
Claim 1 recites that the TCR comprises a CDR3 of the alpha chain comprising an amino acid sequence that is “at least 80% similar” to SEQ ID NO: 12, and/or a CDR3 of the beta chain comprising an amino acid sequence that is “at least 80% similar” to SEQ ID NO: 14, or a CDR3 of the alpha chain comprising an amino acid sequence that is “at least 80% similar” to SEQ ID NO: 40, and/or a CDR3 of the beta chain comprising an amino acid sequence that is “at least 80% similar” to SEQ ID NO: 42.
Based on the recitation of “at least 80% similar” and the use of “and/or” in the claim, claim 1 encompasses a genus of TCRs limited by only single CDR that has at least 80% similarity to one of the recited CDR3s and is claimed as having the recited binding functions.
Claims 4 and 5 further require that the TCR of claim 1 perform the functions of inducing IFN-gamma secretion by cells comprising the TCRs and that the IFN-gamma secretion of the cells comprising the TCR be at least 5-fold higher compared to control cells that do not comprise the TCR.
Claims 14 and 16-20 all further require that the TCR of claim 1, a nucleic acid molecule encoding the TCR, a vector comprising the nucleic acid molecule, or a host cell comprising the TCR perform the claimed function of treating cancer, detecting cancer, or preventing cancer.
As such, claims 4, 5, 14, and 16-20 claim further function of the TCR recited in claim 1, which as discussed above, is limited by only single CDR that has at least 80% similarity to one of the recited CDR3s.
Claim 2 recites that the TCRs according to claim 1 further comprise a CDR1 comprising an amino acid sequence being “at least 80% similar” to those recited “and/or” a CDR2 comprising an amino acid sequence being “at least 80% similar” to those recited. The claim also uses “and/or” with respect to the inclusion of the CDR1 and CDR2 of the beta chain.
Claims 6 and 7 recite alpha chain variable region comprising an amino acid sequence that are “at least 80% similar” to the recited sequences including regions of the sequences being “at least 80% similar” “and/or” beta chain variable regions comprising an amino acid sequence that is “at least 80% similar” to the recited sequences including regions of the sequence being “at least 80% similar”.
Claim 8 recites that the TCR comprises at least one TCR alpha chain “or subregion thereof” and at least one beta chain “or subregion thereof” referencing limitations allowing for at least 80% similarity.
Claim 10 recites a nucleic acid that encodes the TCR according to claim 1 where the nucleic acid sequence is “at least 80% identical” to the nucleic acid sequences recited.
While each of the claims further limit portions of the TCR structure, the claims all remain drawn to a genus of TCRs that do not include a full complement of 6 CDRs and are claimed as having the binding function recited in instant claim 1.
As such, the instant claims are drawn to a genus of TCR binding domains all of which are claimed as having the function of being capable of binding to a polypeptide comprising an amino acid sequence of SEQ ID NO: 2, where not more than 4 amino acids have been substituted or to a portion of said polypeptide, or to the respective HLA-A bound form of said polypeptide or portion thereof.
The instant disclosure, however, does not provide a representative number of species of the claimed genus performing the claimed functions, particularly in the absence of a full complement of 6 CDRs, specifically 3 from the alpha chain variable region and 3 from the beta chain variable region.
The examples of the instant disclosure describe an in vitro priming approach used to isolate PRAME 301-309 specific HLA-A24 restricted TCRs (page 54, Example 1). In the example, monocytes derived from HLA-A*24:02 negative healthy donors and corresponding mDCs were produced using a suitable maturation cocktail and electroporated with ivtRNA encoding for PRAME and the HLA-A*24 molecule. The prepared mDCs were subsequently co-cultured with CD8+ T cells and after 14 days PRAME 301-309 specific T cells were identified and the TCR was sequenced.
The examples detail the evaluation of antigen specificity for TCR T402-93 or TCR T116-49 and discloses that both recognized the specific PRAME 301-309 peptide as well as PRAME-transfected LCL (page 55, lines 15-20). The examples further tested killing mediated by the two TCRs and functional avidity of the TCRs (pages 56-57, Examples 3-4). Example 6 tested recognition of mismatched peptides in which mutations were made in the wild-type peptide of PRAME 301-309 (SEQ ID NO: 2). In table 2 of the example (page 58) there is a list of the five mismatched peptides out of 52 tested peptides that were recognized by either T402-93 or TCR116-49 transgenic T cells.
Table 1 on pages 41-42 disclose that T402-93 and TCR116-49 comprise the following sequences:
PNG
media_image1.png
257
1216
media_image1.png
Greyscale
PNG
media_image2.png
256
1216
media_image2.png
Greyscale
These TCRs, with 100% identity in the full complement of the 6 CDRs (three from the alpha chain and 3 from the beta chain) represent the TCRs that applicant was in possession of at the effective filing date of the claimed invention.
The two TCRs sequenced and tested by applicant in the disclosure are not representative of the entire claimed genus which limits the claimed TCRs by as little as a single CDR (CDR3) with similarity of 80%. The disclosure also does not provide a structure function correlation which would allow for the predictable identification of which TCRs within the claimed genus would perform the claimed function(s).
It is noted that the instant disclosure defines “similar” as meaning that a given amino acid sequence comprises identical amino acids or only conservative or highly conservative substitutions compared to the amino acid sequence of the respective SEQ ID NO. As used herein, “conservative” substitutions mean substitutions as listed as “exemplary substitutions” in Table I and “highly conservative” substitutions mean substitutions as shown under the heading “preferred substitutions” in Table I (page 6).
The disclosure, however, does not demonstrate that any of the substitutions disclosed could be made in the CDRs of the exemplified TCRs while maintaining functionality. Additionally, while the disclosure recognizes these as conservative or highly conservative substitutions, the disclosure does not demonstrate or teach a structure-function correlation that establishes that the substitutions can lead to predictable function.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus. Rather, the art suggests that TCR binding was not predictable such that CDRs could mutated or be paired together resulting in predictable function.
For instance, Wong, W.K., et al (2019) Comparative analysis of the CDR loops of antigen receptors Frontiers in immunology 10(2454); 1-11 teaches that for both antibodies and TCRs, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the “canonical classes”; the remaining CDR (β3 in TCRs and H3 in antibodies) is more structurally diverse (abstract). In TCRs, CDR1 and CDR2 typically contact the MHC’s conserved α-helices, while the CDR3 almost always contacts the peptide antigen. The structural complementarity between the binding sites of the antigen receptor and their cognate antigen governs the binding interactions. As the CDRs form the majority of the binding site, their conformations are critical to the binding (page 2, left column, paragraph 1).
Wong studied canonical forms in TCRs and built an auto-updating sequence-based prediction tool and compared TCR CDRs to antibody CDRs (abstract). Wong teaches that the fact that nearly 20% of the TCR CDRs that could show different conformations did so, suggests that the canonical class model will struggle to accurately predict TCR CDR conformations (page 7, right column, paragraph 5).
Jokinen, E., et al (2021) Predicting recognition between T cell receptors and epitopes within TCRGP PLOS Computational Biology 17(3); e1008814; 1-27 teaches that to initiate an adequate adaptive immune response, a peptide, called an epitope, must first be bound by the major histocompatibility complex (MHC) class I or II molecule expressed on the surface of a nucleated cell or a professional antigen-presenting cell, respectively. The peptide-MHC complex is then presented to T cells which can recognize the complex via the TCR proteins, consequently leading to T cell activation and proliferation (page 2, paragraph 1). The CDRs of a TCR determine whether the TCR recognizes and binds to an antigen or not. Of these, CDR3 is the most variable and primarily interacts with the peptide, while CDR1 and CDR2 primarily interact with the peptide binding groove of the MHC protein presenting the peptide, but they can also be directly in contact with the peptide (page 2, paragraph 3). Jokinen teaches that we can characterize which TCRs recognize certain epitopes experimentally, but this is a time consuming task and is often not possible with scarce patient samples such as biopsies. However, previously produced experimental data has enabled the development of a computational method, TCRGP, that can predict which epitopes a TCR recognizes with higher accuracy than previous methods (abstract). Jokinen; however, teaches that even this model requires a sufficient amount of experimentally produced epitope-specific TCR-sequencing data be available to train a classifier. The exact number of TCRs required to achieve a certain level of accuracy also varies greatly between different epitopes. This likely reflects the fact that different epitopes can be more selective in choosing their TCR interactions. In other words, TCRs that recognize one epitope can be more diverse than the TCRs that recognize another epitope, and, if the TCRs are very heterogenous, it requires more sampling to get a representative sample of these TCRs for the model training. Jokinen teaches that although computational methods cannot replace experimental measurements they may be used to complement them when analyzing existing unselected TCR repertoire data or to guide experimental designs for ex vivo measurements (page 15, paragraph 3). With the currently available epitope-specific TCR sequence data we have come this far, but as more data becomes available with modern high-throughput techniques presented recently, new possibilities will rise. With a larger variety of pMHC complexes and TCRs that recognize them, we hope to better consider the cross-reactivity of TCRs, similarities between epitopes, and the significance of the HLA-types of the MHC proteins presenting the epitopes, and perhaps even predict if a TCR can recognize a previously unseen epitope (page 15, paragraph 4).
The teachings of Wong and Jokinen demonstrate that the binding function of TCRs depends on the full complement of 6 CDRs, specifically 3 from the α chain and 3 from the β chain, and that, while strides had been made towards predictability, it was still not possible to predictably determine binding specificity of CDRs without experimental measurements. As such, one of ordinary skill in the art would not have been capable of predictably identifying which species of the claimed genus, would be capable of retaining the claimed functions. Additionally, as discussed by Wong and Jokinen, immune response, and therefore therapeutic outcomes, result from the recognition of a peptide in complex with MHC; a recognition which relies on the binding of a full complement of six CDRs.
The art also suggests that even conservative substitutions do not lead to predictable function when used in binding domains. For example, Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22 demonstrates that even approximately 2 years after the effective filing date of the claimed invention, conservative substitution of amino acids in binding domains was not predictable. Rojas studied manipulation of antibody-antigen interactions through combinatorial biology (page 2, paragraph 2). Rojas teaches that “epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the differences between amino acids, based on physico-chemical distance between them, mutational distance (determined by the genetic code and mutational biases) or in evolutionary exchangeability (how often a given residue is replaced by another one in conserved protein families)… the critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody” (page 11, paragraph 1). These teachings of Rojas demonstrate that even limiting structure variation to conservative substitutions is not enough to establish a predictable structure-function relationship when it comes to antigen binding domains.
It is not evident from the instant disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the full scope of the genus of TCRs encompassed by the instant claims. Additionally, there is no disclosed or art recognized structure-function relationship that would allow one of ordinary skill in the art to predictably identify which CDR sequences could be used with what other structures resulting in the claimed functions of acting as a TCR while being capable of binding to a polypeptide comprising an amino acid sequence according to SEQ ID NO: 2 wherein not more than 4 amino acids have been substituted or a portion thereof, or in a method of treating, preventing, or diagnosing cancer. Therefore, the instant claims were found not to meet the written description requirement.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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 14, 16-18, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for therapeutic treatment or amelioration of diseases, does not reasonably provide enablement for prophylactic treatment or prevention. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instant claims are drawn to methods of treating cancer (claims 14 and 16-18) or preventing cancer (claim 20) in a human or non-human mammal comprising administering a TCR, nucleic acid molecule encoding a TCR, vector comprising the nucleic acid molecule, or a host cell comprising the TCR, to the subject.
The breadth of the claims
The claims are broad in that they encompass the prophylactic treatment or prevention of cancer.
The instant specification states that “The term ‘treatment’ in all its grammatical forms includes therapeutic or prophylactic treatment of a subject in need thereof. A ‘therapeutic or prophylactic treatment’ comprises prophylactic treatments aimed at the complete prevention of clinical and/or pathological manifestations or therapeutic treatment aimed at amelioration or remission of clinical and/or pathological manifestations. The term ‘treatment’ thus also includes the amelioration or prevention of diseases.”
The specification does not provide a limiting definition for “prevention”. In absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure studied TCRs T402-93 and T116-49 including antigen specificity (page 55, Example 2) and tumor cell recognition (page 55, Example 3). The examples demonstrate that the TCRs were capable of recognizing the specific PRAME 301-309 peptide as well as PRAME-transfected LCL (page 55, lines 15-20). Additionally, the examples assessed mediated killing by TCR transgenic T cells using two PRAME-positive tumor cell lines (Mel624.38, SKHEP1) and a PRAME-negative tumor cell line (Colo678) as target cells. Red-labelled tumor cells were seeded in plates two days prior ot the start of co-culture. After adding 10000 T cells expressing either of the TCRs, the culture plates were transferred to a live imaging system and monitored over a total period of 105h to assess killing. The experiment discloses that both TCR transduced samples effected growth of Mel624.38 PRAME-positive cell lines while only TCR T116-49 transduced T cells mediated efficient killing of the SKHEP1 PRAME-positive cell line.
The examples do not demonstrate prevention of cancer nor does the examples demonstrate a method that could be used to predictably identify that a subject would have gotten cancer without the treatment in order to establish that the cancer was prevented.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that can be used to predictably determine that cancer onset was prevented using claimed method or to identify patients who would predictably develop cancer in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the state of the art indicates that cancer development was not predictable.
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors had been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
Cuzick, J. (2017) Preventive therapy for cancer Lancet Oncol 18; e472- e482 teaches the use of therapeutic preventative measures in addition to weight control and physical activity, such as low-dose aspirin for adults without the risk of hypertension or gastrointestinal bleeding, universal HPV vaccination, and other therapies such as anti-oestrogen drugs for breast cancer prevention targeting high-risks groups to “maintain a favorable benefit-risk ratio” (abstract). While Cuzick is identifying therapeutic regimens to prevent cancer, Cuzick also teaches “the balance of risks and benefits is inherently more challenging for preventative than for therapeutic interventions. Only a small fraction of the apparently healthy people who receive a preventative treatment would ultimately develop the specific type of cancer being targeted. Moreover, the absence of the cancer is not quantifiable at an individual level, whereas all those treated will incur a risk of side-effects which are identifiable on an individual basis” (page e472, left column, paragraph 2).
Cuzick demonstrates that the prevention of cancer is not predictable and that numerous factors contribute to the development of cancer. Additionally, Cuzick teaches difficulties in preventing cancer with therapeutic methods and specifically states that the absence of cancer is not quantifiable on an individual level, a statement which demonstrates that the determination of whether or not cancer was prevented is unpredictable.
DeCensi, A., et al (2015) Barriers to preventative therapy for breast and other major cancers and strategies to improve uptake ecancer 9(595); 1-12 teaches that the global cancer burden continues to rise but the utilization of preventative therapy has been poor due to various barriers. DeCensi teaches barriers such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. DeCensi provides a review discussing the barriers and proposes strategies to overcome them including improving awareness and countering prejudices by highlighting the important differences between preventative therapy and cancer treatment. DeCensi further teaches that future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms and improvements in safety profiles of existing agents by experimentation with dose (abstract). DeCensi teaches that for preventative therapy, we cannot identify individuals whose cancer was prevented or risk was substantially reduced because of the lack of measurable biomarkers of efficacy that currently exist for other diseases such as cardiovascular diseases, prevention of diabetes complications or osteoporotic bone fractures. Therefore, from that person’s point of view, they either took medication unnecessarily or, in the worst-case scenario, unnecessarily suffered the adverse effects of such therapy (page 2, paragraph 1).
The teachings of DeCensi demonstrate that, while preventative therapies could be beneficial if various barriers are overcome, there was no method known that could be used to identify individuals whose cancer was prevented because of the lack of measurable biomarkers.
The teachings of Lewandowska, Cuzick, and DeCensi demonstrate that there was no art recognized method of determining whether a patient would predictably develop cancer and, therefore, there is no predictable way to determine that cancer was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a mammal would have predictably developed cancer in order to apply the claimed treatment as a preventative measure. Furthermore, there is no known or disclosed method that could be used to establish that cancer was prevented as there is no predictable way to know that the subject being treated would have developed a cancer without the treatment. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to establish that cancer was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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, Joanne Hama can be reached on 571-272-2911. 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.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693