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 .
1. Claims 1-18 are pending and being examined.
Claim Objections
2. Claim 1 is objected to because of the following informalities: claim 1 contains a typo and recites “at least one least one”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 1-18 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.
Claim 1 recites the limitation: “the one or more synthetic DNA encoded bispecific immune cell engager”. There is insufficient antecedent basis for this limitation in the claim. Dependent claims 2-18 are rejected for encompassing the rejected limitation of claim 1.
Claim 6 recites: “The nucleic acid molecule of claim 5, wherein the binding fragment comprises…”. It is unclear which binding fragment claim 6 is referencing because there are two different binding fragments recited in claim 5.
Claim 7 recites: “The nucleic acid molecule of claim 5, wherein the binding fragment comprises…”. It is unclear which binding fragment claim 7 is referencing because there are two different binding fragments recited in claim 5.
Claim 9 recites: “The nucleic acid molecule of claim 8, wherein the fragment encodes…”. It is unclear which fragment claim 9 is referencing because there are two different fragments recited in claim 8.
Claim 10 recites: “The nucleic acid molecule of claim 8, wherein the fragment encodes…”. It is unclear which fragment claim 10 is referencing because there are two different fragments recited in claim 8.
Claim 15 recites: “the method comprising administering to the subject a nucleic acid molecule of claim 1 or a composition comprising the same”. The claim is unclear with regard to what “the same” encompasses. The metes and bounds of the claimed invention cannot be determined.
Claim Interpretation
4. Examiner is applying the broadest reasonable interpretation to claims 5-10 as follows:
Claim 5 a) encompasses a genus of nucleic acid molecules encoding an amino acid sequence of any length having around 90% or more identity over its entire length to any amino acid sequence selected from SEQ:2, 4, 6, and 8, including amino acid sequences as few as two consecutive amino acids long selected from SEQ ID NOs:2, 4, 6, or 8.
Claim 5 b) encompasses a genus of nucleic acid molecules encoding any binding fragment of an amino acid sequence of any length having around 90% or more identity over at least 65% of any amino acid sequence found in SEQ ID NOs:2, 4, 6, or 8; and wherein the binding function of the binding fragment is not defined.
Claim 5 c) encompasses a genus of nucleic acid molecules encoding any amino acid sequence (“an amino acid sequence”) selected from SEQ ID NOs:2, 4, 6, or 8 that comprises as few as two consecutive amino acids found in SEQ ID Nos:2, 4, 6, or 8.
Claim 5 d) encompasses a genus of nucleic acid molecules encoding a binding fragment of any amino acid sequence of any length comprising at least 65% of any amino acid sequence found in SEQ ID NO:2, 4, 6, or 8, and wherein the binding function of the binding fragment is not defined.
Claim 6 encompasses a genus of nucleic acid molecules encoding a binding fragment comprising at least six CDR sequences of any amino acid sequence selected from SEQ ID NOs:2, 4, 6, or 8; and wherein the binding function and CDR sequences are not defined.
Claim 7 encompasses a genus of nucleic acid molecules encoding a binding fragment comprising at least twelve CDR sequences of any amino acid sequence selected from SEQ ID NOs:2, 4, 6, or 8; and wherein the binding function and CDR sequences are not defined.
Claims 8-10 comprise similar language to claims 5-7 and encompass a vast genus of nucleic acids for the reasons stated above.
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.
5. Claims 1-18 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a nucleic acid molecule encoding one or more synthetic DNA encoded bispecific therapeutic antibodies, or a binding fragment thereof, wherein the one or more synthetic DNA encoded bispecific immune cell engager comprises at least one antigen binding domain specific for binding to IL13Rα2, and at least one immune cell engaging domain. Dependent claims 2-4 require the immune cell engaging domain target a specific cell type or T cell receptor such as CD3. Claims 15-18 require the nucleic acid molecule to function by treating or preventing a disease or disorder, wherein the disease is a benign tumor, cancer, or cancer-associated disease, such as glioblastoma. Thus, the claims appear to identify the antibody encoded by the nucleic acid molecule by function only, where the function is to bind IL13Rα2 and engage or target an immune cell, such as by targeting CD3. No antibody sequence structure is recited.
Dependent claims 5-7 recite a partial sequence structure of the antibody encoded by the nucleic acid. The nucleic acid can encode:
a) an amino acid sequence having at least about 90% identity over an entire length of the amino acid sequence to an amino acid sequence selected from SEQ ID NOs:2, 4, 6, and 8;
b) a binding fragment of an amino acid sequence having at least about 90% identity over at least 65% of the amino acid sequence to an amino acid sequence selected from SEQ ID NOs:2, 4, 6, and 8;
c) an amino acid sequence selected from SEQ ID NOs:2, 4, 6, and 8; or
d) a binding fragment of an amino acid sequence comprising at least 65% of an amino acid seque3nce selected from SEQ ID NOs:2, 4, 6, and 8 (claim 5);
wherein the binding fragment of b) comprises at least six CDR sequences of an amino acid sequence selected from SEQ ID NOs:2, 4, 6, 8 (claim 6); and
wherein the binding fragment of b) comprises at least twelve CDR sequences of an amino acid sequence selected from SEQ ID NOs:2, 4, 6, 8 (claim 7).
Dependent claims 8-10 recite a partial sequence of the nucleic acid molecule encoding the bispecific therapeutic antibodies, wherein the nucleic acid molecule:
a) has at least about 90% identity over an entire length of the nucleic acid sequence to a nucleotide sequence selected from SEQ ID NOs:1, 3, 5, and 7;
b) is a fragment of a nucleotide sequence having at least about 90% identity over at least 65% of the nucleic acid sequence to a nucleotide sequence selected from SEQ ID NOs:1, 3, 5, and 7;
c) is a nucleotide sequence selected from the group consisting of SEQ ID NOs:1, 3, 5, and 7; or
d) is a fragment of a nucleotide sequence comprising at least 65% of a nucleotide sequence selected from SEQ ID NOs:1, 3, 5, and 7 (claim 8);
wherein the fragment of b) encodes at least six CDR sequence of an amino acid sequence selected from SEQ ID NOs:2, 4, 6, and 8 (claim 9); and
wherein the fragment of b) encodes twelve CDR sequences of an amino acid sequence selected from SEQ ID NOs:2, 4, 6, and 8 (claim 10).
Claims 5-10 encompass a vast genus of nucleic acid molecule sequence variants comprising any sequence found in SEQ ID NOs:1, 3, 5, and 7; encoding any sequence found in SEQ ID NOs:2, 4, 6, and 8; and comprising six or 12 unidentified CDR sequences. See Claim Interpretation section above.
The instant specification discloses four exemplary bispecific therapeutic antibodies that bind to both IL13Rα2 and CD3, represented by amino acid SEQ ID NOs:2, 4, 6, and 8, encoded by nucleic acid SEQ ID NOs:1, 3, 5, and 7, respectively (Table 1):
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The instant specification discloses that SEQ ID NOs:2, 4, 6, and 8 comprise anti-IL13Rα2 antibody PB01-Forward, PB01-Reverse, PB02-Forward, and PB02-Reverse, respectively, each fused to UCHT1 anti-CD3 antibody (see Examples and all Figures). The specification discloses:
[0277] dBTE design:
[0278] The heavy and light chain sequences were derived from humanized antibodies as described in (Yin et al., 2018, Molecular Therapy Oncolytics, 11:20-38). The heavy and light chains of IL13Rα2 targeting antibodies were fused to heavy and light chains of a modified UCHT1 antibody via GS linkers. All sequences were codon optimized and encoded in a non-replicating pVax vector (FIG. 1A, Table 1).
The specification does not identify the CDR sequences found within SEQ ID NOs:2, 4, 6, and 8.
The specification demonstrates that PB01-Forward successfully treats tumors expressing IL13Rα2 including brain tumors as a dBTE (DNA-launched bispecific T cell engager) targeting both IL13Rα2 and CD3 (Examples, Figures 14-16).
Thus, the instant specification describes four dBTE antibody sequences, SEQ ID NOs:2, 4, 6, and 8, that function to bind IL13Rα2, target CD3, and treat cancer/glioblastoma as claimed. The specification fails to disclose the structural sequence required of any other bispecific antibody to possess the function of binding IL13Rα2 and targeting any other immune cell or immune cell target, and treating cancer/glioblastoma as claimed.
To provide adequate written description and evidence of possession of the claimed antibody genus and encoding nucleic acid molecule, the instant specification can structurally describe representative bispecific antibodies that function to bind IL13Rα2 and target CD3 or other immune cells or immune cell receptor molecules, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the antibody function: binding IL13Rα2, and an immune cell engaging domain that targets immune cells, targets CD3, or targets other T cell receptors; and wherein the antibody treats disease or disorders. Although dependent claims 5-10 recite a partial sequence structure, the claims do not recite or require the sequence critical to performing the claimed antibody functions. The claims and specification do not identify the CDR sequences. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only four representative bispecific antibody sequences that function to bind IL13Rα2 and CD3 and treat cancer as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for SEQ ID NOs:2, 4, 6, and 8, encoded by nucleic acid SEQ ID NOs:1, 3, 5, and 7, respectively, the specification fails to provide the structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequences for the vast genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to perform the claimed method.
In the instant case, the specification discloses four representative bispecific antibody SEQ ID NOs:2, 4, 6, and 8 that function as claimed. The specification does not disclose the sequence structure of any antibody sequence variants comprising less than 100% of SEQ ID NOs:2, 4, 6, and 8 that would predictably function as claimed. The claims broadly encompass any bispecific antibody sequence variants required to function as claimed. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain IL13Rα2 binding and immune cell targeting function and treat diseases or disorders such as cancer and glioblastoma. The instant claims attempt to claim a nucleic acid molecule encoding every bispecific antibody that would achieve a desired result, i.e., bind IL13Rα2 and engage an immune cell, wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only four exemplary sequences of bispecific PB01 or PB02 anti-IL13Rα2 X UCHT1 anti-CD3 antibodies. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of the four disclosed antibody sequences to the structure of any and all anti-IL13Rα2 immune cell engaging bispecific antibodies, as broadly claimed and required to practice the claimed methods. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for antibodies that bind IL13Rα2 or engage an immune cell and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The IL13Rα2 and immune cell surface antigens provide no information about the structure of an antibody that binds to them.
Given the lack of representative examples to support the full scope of the claimed nucleic acid molecules encoding antibodies used in the claimed method, and lack of reasonable structure-function correlation with regards to the unknown sequences in the CDRs that provide the functions of binding IL13Rα2, engaging or targeting immune cells, and treating cancer, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the bispecific therapeutic antibodies and their encoding nucleic acid molecules that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Amend claim 1 to recite:
A nucleic acid molecule encoding a bispecific antibody that binds to IL13Rα2 and CD3, the antibody comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2, 4, 6, and 8.
Or
A nucleic acid molecule encoding a bispecific antibody that binds to IL13Rα2 and CD3, the nucleic acid molecule comprising the nucleotide sequence selected from the group consisting of SEQ ID NOs:1, 3, 5, and 7.
6. Claims 15-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer expressing IL13Rα2 in a subject, the method comprising administering to the subject a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs:1, 3, 5, and 7, does not reasonably provide enablement for methods for preventing any disease, disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). 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.
The claims encompass methods of preventing diseases, disorders, cancer, and glioblastoma in a subject comprising administering the nucleic acid molecule of claim 1 to the subject.
The specification discloses administering a nucleic acid molecule encoding PB01-Forward (IL13Rα2 X UCHT1 CD3) bispecific T cell engager antibody and T cells to tumor models and successfully treating the tumors by specific or non-specific killing, wherein the tumors express IL13Rα2 antigen (U87 tumors) or do not (OVCAR3) (Examples; Figures 14-16). The specification does not demonstrate any predictable prevention of cancer, diseases, or disorders by administering the bispecific T cell engager. A high quantity of experimentation would be required to determine what diseases, disorders, and cancers the claimed nucleic acid molecule can prevent.
In relevant art, CN107880131, Zhou et al, published 2018 (English translation of specification and claims provided) teaches a bispecific T cell engager (BTE or BiTE) antibody comprising a binding domain to IL13Rα2 and a binding domain to CD3, encoded by a nucleic acid, wherein the nucleic acid is comprised in an expression vector and a composition comprising a pharmaceutically acceptable carrier (English translation p. 2; Examples 1 and 2; claims 1-10). Zhou successfully demonstrates killing glioblastoma cells expressing IL13Rα2 (U251) by administering the BTE in conjunction with T cells (Example 4). Zhou demonstrates that the BTE had a weak killing effect on control 293T cells that do not express IL13Rα2 (p. 6; Example 4). Zhou does not demonstrate disease, disorder, or cancer prevention by administering a nucleic acid encoding the BTE.
Zannikou et al (Neuro-Oncology, Volume 21, Issue Supplement_3, August 2019, Pages iii59–iii60) teaches administering a IL13Rα2 X CD3 BiTE to successfully treat IL13Rα2-expressing glioblastoma, resulting in significant survival benefit and higher frequency of intratumoral CD8+ T cells. Zannikou teaches the BiTE induces a potent cytotoxic activity of CD3+ T cells against IL13Rα2+ glioma cells. Zannikou does not demonstrate disease, disorder, or cancer prevention by administering a nucleic acid encoding the BTE.
Perales-Puchalt et al (Journal of Cancer Institute, 2019, 4(8):e126086, internet pages 1-8) demonstrates that DNA-encoded BiTEs (dBiTEs) targeting a tumor antigen and CD3 (derived from UCHT1) are highly cytolytic and delayed tumor progression for tumors expressing the targeted tumor antigen (abstract; Methods; Figure 3 and 4). Perales-Puchalt demonstrates tumor growth is significantly impaired by administration of the dBiTE, compared to negative control treatments (Figure 4), however, Perales-Puchalt does not demonstrate the dBiTE can prevent any diseases, disorders, or cancers.
Regarding the prevention of cancer, disease and disorder, the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer, disease, and disorder. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer, disease, or disorder, or have had cancer, disease or disorder. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and Iink those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the claimed nucleic acid molecule encoding the IL13Rα2 bispecific immune cell engager, will predictably function as claimed.
Therefore, in view of the novel nature of the invention, what is unknown in the art because of the novel nature of the invention, the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples for prevention, it would require undue experimentation for one skilled in the art to practice the invention as claimed.
Examiner Suggestion: Delete “preventing or” from claim 15.
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.
7. Claim(s) 1-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent Application Publication 2016/0017058, Kim et al.
Kim teaches a bispecific T cell engager antibody comprising a binding domain to IL13Rα2 and a binding domain to CD3 (claims 1, 9; [7-8]; [99]; [101]; [103]; [214]);
wherein the CD3 binding domain is UCHT1 or a CD3-bidning fragment thereof ([20]; [82]; Figure 1), and comprises light chain SEQ ID NO:1 and heavy chain SEQ ID NO:2 (Table 10) that appear to comprise the same six CDR regions as instant SEQ ID NO:2 UCHT1 region (see sequence alignments below); and wherein SEQ ID NOs:1 and 2 of Kim comprise a sequence 100% identical to an amino acid sequence selected from SEQ ID NO:2 (see sequence alignments below).
Kim teaches nucleic acid molecules encoding the bispecific antibody ([87]; [89]; [91]; [109]; [111]; [113]).
Instant SEQ ID NO:2 aligned with Kim UCHT1 anti-CD3 light chain SEQ ID NO:1:
QY = instant SEQ ID NO:2
DB = Kim SEQ ID NO:1
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Instant SEQ ID NO:2 aligned with Kim UCHT1 anti-CD3 heavy chain SEQ ID NO:2:
QY = instant SEQ ID NO:2
DB = Kim SEQ ID NO:2
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8. Claim(s) 1-4, 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CN107880131, Zhou et al, published 2018 (English translation of specification and claims provided).
Zhou teaches a bispecific T cell engager antibody comprising a binding domain to IL13Rα2 and a binding domain to CD3, encoded by a nucleic acid, wherein the nucleic acid is comprised in an expression vector and a composition comprising a pharmaceutically acceptable carrier (English translation p. 2; Examples 1 and 2; claims 1-10).
9. Claim(s) 1-4, 12, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zannikou et al (Neuro-Oncology, Volume 21, Issue Supplement_3, August 2019, Pages iii59–iii60).
Zannikou teaches a composition comprising a vector comprising a nucleic acid encoding a bispecific T cell engager (BiTE) that binds to IL13Rα2 and CD3.
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.
10. Claim(s) 1-6, 8, 9, and 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2016/0017058, Kim et al; in view of CN107880131, Zhou et al, published 2018 (English translation of specification and claims provided); Zannikou et al (Neuro-Oncology, Volume 21, Issue Supplement_3, August 2019, Pages iii59–iii60); and Perales-Puchalt et al (Journal of Cancer Institute, 2019, 4(8):e126086, internet pages 1-8).
Kim teaches a bispecific T cell engager (BTE or BiTE) antibody comprising a binding domain to IL13Rα2 and a binding domain to CD3 (claims 1, 9; [7-8]; [99]; [101]; [103]);
wherein the CD3 binding domain is UCHT1 or a CD3-bidning fragment thereof ([20]; [82]; Figure 1), and comprises light chain SEQ ID NO:1 and heavy chain SEQ ID NO:2 (Table 10) that appear to comprise the same CDR regions as instant SEQ ID NO:2 (see sequence alignment below);
and nucleic acid molecules encoding the bispecific antibody ([[87]; [89]; [91]; [109]; [111]; [113]).
Kim teaches methods of treating a glioblastoma expressing IL13Rα2 in a subject, the method comprising administering the bispecific antibody ([214]).
Kim does not teach:
a nucleic acid sequence having 100% identity to the regions in instant SEQ ID NO:3 encoding the identical anti-CD3 antibody amino acid sequences and six CDRs (claims 8 and 9);
administering a nucleic acid molecule encoding the bispecific antibody to the subject to treat glioblastoma (claims 15-18);
a pharmaceutical composition or vector comprising the nucleic acid molecule (claims 12-14); or
the nucleic acid sequence encoding the BTE comprises an IgE leader sequence (claim 11).
Zhou teaches a bispecific T cell engager (BTE or BiTE) antibody comprising a binding domain to IL13Rα2 and a binding domain to CD3, encoded by a nucleic acid, wherein the nucleic acid is comprised in an expression vector and a composition comprising a pharmaceutically acceptable carrier (English translation p. 2; Examples 1 and 2; claims 1-10). Zhou teaches and successfully demonstrates killing glioblastoma cells expressing IL13Rα2 by administering the BTE in conjunction with T cells (Example 4).
Zannikou teaches a composition comprising a vector comprising a nucleic acid encoding a bispecific T cell engager (BTE or BiTE) that binds to IL13Rα2 and CD3. Zannikou teaches administering the BiTE to treat successfully IL13Rα2-expressing glioblastoma, resulting in significant survival benefit and higher frequency of intratumoral CD8+ T cells.
Perales-Puchalt teaches advantages for administering DNA encoding bispecific T cell engagers (BiTEs or BTEs) over the administering the BiTEs themselves. Perales-Puchalt teaches and demonstrates that DNA-encoded BiTEs (dBiTEs) targeting a tumor antigen and CD3 (derived from UCHT1) are highly cytolytic and delayed tumor progression (abstract; Methods; Figure 3 and 4). Perales-Puchalt teaches problems with BiTEs such as slow development timelines, limited modification options, and short half-life for the molecules, requiring frequent repeat administrations. Perales-Puchalt teaches DNA-encoded BiTEs (dBiTEs) permit simplified development, delivery, and in vivo production, with higher expression, longer expression, and longer half-life (Introduction; Figures 3 and 4; Discussion). Perales-Puchalt demonstrates making the dBiTE with IgE leader sequences for high expression (Figure 1A and 4A; Methods).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce a nucleic acid sequence having 100% identity to the regions in instant SEQ ID NO:3 encoding the identical anti-CD3 antibody UCHT1 amino acid sequences and six CDRs. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Kim teaches a nucleic acid sequence encoding the bispecific antibody comprising the same anti-CD3 UCHT1 binding region instantly claimed; (2) Kim teaches the known amino acid sequences encoding the same CD3 binding region instantly claimed; (3) Zhou, Zannikou, and Perales-Puchalt teach the technology for making nucleic acids encoding BTEs is established; and (4) one of ordinary skill in the art, due to the limited degeneracy code, could readily and predictably arrive at the instantly claimed nucleic acid sequences encoding the same antibody binding regions.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the bispecific antibody of Kim as DNA to treat glioblastoma. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Kim, Zhou, and Zannikou teach or demonstrate BTEs targeting IL13Rα2 and CD3 successfully treat glioblastoma, wherein the BTE of Kim comprises a CD3 binding domain derived from known UCHT1 anti-CD3 antibody; (2) Perales-Puchalt teach administration of DNA encoding the BTE is advantageous over administering the BTE protein because of its easier production, in vivo delivery, higher expression, longer expression, and longer half-life; and (3) Perales-Puchalt demonstrates that a tumor-targeting BTE comprising a CD3 binding domain derived from UCHT1 successfully treated cancer, was highly cytolytic, and delayed tumor progression.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to formulate a nucleic acid encoding the bispecific antibody of Kim in a vector or pharmaceutical composition comprising a pharmaceutically acceptable carrier. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Kim, Zhou, and Zannikou teach or demonstrate making nucleic acid molecules encoding the BTE; (2) Zhou and Zannikou successfully demonstrate their BTE nucleic acid molecule comprised in a vector for expression; and (3) Perales-Puchalt suggests and demonstrates making pharmaceutical compositions with acceptable carriers comprising DNA and vectors encoding BTE for the treatment of cancer.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add an IgE leader sequence to the nucleic acid sequence encoding the BTE. One would have been motivated to, and have a reasonable expectation of success to, because Perales-Puchalt demonstrates successfully doing so for high BTE expression, and IgE leader sequences are known in the art for allowing high expression and secretion of encoded proteins.
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.
11. Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6-10, 13, 15, 16, 18-21, 23-28 of copending Application No. 18/855,100 (reference application), in view of CN107880131, Zhou et al, published 2018 (English translation of specification and claims provided); Zannikou et al (Neuro-Oncology, Volume 21, Issue Supplement_3, August 2019, Pages iii59–iii60); and Perales-Puchalt et al (Journal of Cancer Institute, 2019, 4(8):e126086, internet pages 1-8).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application is claiming a composition comprising a nucleic acid sequence encoding a bispecific antibody binding to IL13Rα2 and CD3, wherein the binding arm to IL13Rα2 is SEQ ID NO:4 that is 100% identical to the anti-IL13Rα2 comprised in instant SEQ ID NO:4 and comprises the MDWTWILFLVAAATRVHS IgE leader sequence, wherein the binding arm to CD3 is SEQ ID NO:2 that is 100% identical to the anti-CD3 antibody comprised in instant SEQ ID NO:4 (see sequence alignments below), therefore the bispecific antibody of the copending application comprises the twelve CDRs of instant SEQ ID NO:4. The copending application further claims the composition comprises a pharmaceutically acceptable carrier. The copending application further claims a method of treating a disease, disorder, cancer, or glioblastoma in a subject, the method comprising administering to the subject the bispecific antibody binding to IL13Rα2 and CD3.
The copending application claims compositions comprising a nucleic acid sequence encoding the same anti-IL13Rα2 and anti-CD3 amino acid sequences instantly claimed, but the copending application does not claim the nucleic acid sequence comprises nucleotide sequences having 100% identity to instant SEQ ID NO:3 encoding the same antibodies; does not claim a vector comprising the nucleic acid; and does not claim administering the nucleic acid encoding the bispecific antibody.
Zhou, Zannikou, and Perales-Puchalt teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce a nucleic acid sequence having 100% identity to the regions in instant SEQ ID NO:3 encoding the identical antibody amino acid sequences. One would have been motivated to, and have a reasonable expectation of success to, because: the copending application claims nucleic acid sequences encoding the bispecific antibody comprising the same IL13Rα2 and CD3 binding regions instantly claimed; the copending application claims the known amino acid sequences encoding the same IL13Rα2 and CD3 binding regions instantly claimed; and one of ordinary skill in the art, due to the limited degeneracy code, could readily and predictably arrive at the instantly claimed nucleic acid sequences encoding the same antibody binding regions.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to formulate the nucleic acid encoding the bispecific antibody of the copending application in a vector. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Zhou and Zannikou demonstrate making nucleic acid molecules encoding a IL13Rα2 x CD3 BTE; (2) Zhou and Zannikou successfully demonstrate their BTE nucleic acid molecule comprised in a vector for expression; and (3) Perales-Puchalt suggests and demonstrates making pharmaceutical compositions with acceptable carriers comprising DNA and vectors encoding BTE for the treatment of cancer.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the bispecific antibody of the copending application as DNA to treat glioblastoma. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the copending application claims administering the BTE for treatment of cancer or glioblastoma; (2) Zhou and Zannikou teach or demonstrate BTEs targeting IL13Rα2 and CD3 successfully treat glioblastoma; (3) Perales-Puchalt teach administration of DNA encoding the BTE is advantageous over administering the BTE protein because of its easier production, in vivo delivery, higher expression, longer expression, and longer half-life; and (4) Perales-Puchalt demonstrates that a tumor-targeting BTE comprising a CD3 binding domain derived from UCHT1 successfully treated cancer, was highly cytolytic, and delayed tumor progression.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant SEQ ID NO:4 aligned with 18/855,100 anti-IL13Rα2 antibody SEQ ID NO:4:
QY = instant SEQ ID NO:4
Db= copending application SEQ ID NO:4
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612
632
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Instant SEQ ID NO:4 aligned with 18/855,100 anti-CD3 antibody SEQ ID NO:2:
QY = instant SEQ ID NO:4
Db= copending application SEQ ID NO:2
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528
622
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12. Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 21, 23, and 24 of copending Application No. 18/855,105 (reference application), in view of CN107880131, Zhou et al, published 2018 (English translation of specification and claims provided); Zannikou et al (Neuro-Oncology, Volume 21, Issue Supplement_3, August 2019, Pages iii59–iii60); and Perales-Puchalt et al (Journal of Cancer Institute, 2019, 4(8):e126086, internet pages 1-8).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending application is claiming a composition comprising a nucleic acid sequence encoding a bispecific antibody binding to IL13Rα2 and CD3, wherein the binding arm to IL13Rα2 is SEQ ID NO:8 that is 100% identical to the anti-IL13Rα2 comprised in instant SEQ ID NO:4 and comprises the MDWTWILFLVAAATRVHS IgE leader sequence, wherein the binding arm to CD3 is SEQ ID NO:2 that is 100% identical to the anti-CD3 antibody comprised in instant SEQ ID NO:4 (see sequence alignments below), therefore the bispecific antibody of the copending application comprises the twelve CDRs of instant SEQ ID NO:4. The copending application further claims the composition comprises a pharmaceutically acceptable carrier. The copending application further claims a method of treating a disease, disorder, cancer, or glioblastoma in a subject, the method comprising administering to the subject the nucleic acid composition encoding the bispecific antibody binding to IL13Rα2 and CD3.
The copending application claims compositions comprising a nucleic acid sequence encoding the same anti-IL13Rα2 and anti-CD3 amino acid sequences instantly claimed, but the copending application does not claim the nucleic acid sequence comprises nucleotide sequences having 100% identity to instant SEQ ID NO:3 encoding the same antibodies; and does not claim a vector comprising the nucleic acid.
Zhou, Zannikou, and Perales-Puchalt teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce a nucleic acid sequence having 100% identity to the regions in instant SEQ ID NO:3 encoding the identical antibody amino acid sequences. One would have been motivated to, and have a reasonable expectation of success to, because: the copending application claims nucleic acid sequences encoding the bispecific antibody comprising the same IL13Rα2 and CD3 binding regions instantly claimed; the copending application claims the known amino acid sequences encoding the same IL13Rα2 and CD3 binding regions instantly claimed; and one of ordinary skill in the art, due to the limited degeneracy code, could readily and predictably arrive at the instantly claimed nucleic acid sequences encoding the same antibody binding regions.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to formulate the nucleic acid encoding the bispecific antibody of the copending application in a vector. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Zhou and Zannikou demonstrate making nucleic acid molecules encoding a IL13Rα2 x CD3 BTE; (2) Zhou and Zannikou successfully demonstrate their BTE nucleic acid molecule comprised in a vector for expression; and (3) Perales-Puchalt suggests and demonstrates making pharmaceutical compositions with acceptable carriers comprising DNA and vectors encoding BTE for the treatment of cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant SEQ ID NO:4 aligned with 18/855,105 anti-IL13Rα2 antibody SEQ ID NO:8:
QY = instant SEQ ID NO:4
Db= copending application SEQ ID NO:8
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616
642
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Instant SEQ ID NO:4 aligned with 18/855,105 anti-CD3 antibody SEQ ID NO:2:
QY = instant SEQ ID NO:4
Db= copending application SEQ ID NO:2
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536
624
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13. Conclusion: No claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
Prosecution Insights