DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 167, 169-175 and 177-189 are pending and under examination.
Applicant elected a heavy chain variable domain of (iv) comprising a CDR1 having the amino acid sequence set forth in SEQ ID NO:217, a CDR2 having the amino acid sequence set forth in SEQ ID NO:218, and a CDR3 having the amino acid sequence set forth in SEQ ID NO:219.
The Declaration of Dr Haifeng has been considered and is discussed below.
35 USC § 112(b) rejections maintained.
The rejections of claims 167, 169-175 and 177-189 on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984) are maintained. A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the different polypeptides is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use.
Applicant’s argue that it is procedurally incorrect to apply an Improper Markush Group rejection under 35 U.S.C. § 112(b) because Improper Markush grouping rejection is a judicially created doctrine and does not have any statutory basis. In In re Weber and In re Haas, the Court of Customs and Patent Appeals held that there was no statutory basis to reject a single claim for an "improper Markush grouping."
In response, the Court in In re Weber stated that there was no statutory basis for rejecting a claim under 35 U.S.C. 121. The Court stated that “since the Markush rejection is inextricably intertwined with the § 121 rejection, we make no decision on the propriety of the Markush rejection and remand to the board for its consideration. However, the result of any such consideration must be consistent with our analysis of an applicant's rights under the second paragraph of 35 U.S.C. § 112.”. The Court further states that section 121 nowhere uses the words "embraced" or "covered." It says "claimed," and that I take to mean what it has always referred to in the terminology of the patent law, a "claim" or definitional paragraph which, in the words of § 112, second paragraph, is "particularly pointing out and distinctly claiming the subject matter the applicant regards as his invention."
In addition, Applicant’s argue that the polypeptides of Claim 167 share both a single structural similarity, specifically, all are single domain antibodies (VH) have a high degree of sequence similarity; and share a common use that flows from the substantial structural feature, specifically, to bind ILlRAP thereby providing an improved therapeutic targeting agent for cancers that express ILlRAP. The polypeptides of Claim 167 relate to single domain antibodies (VH) having a high degree of sequence similarity. A sequence alignment of the seven claimed polypeptides, 3A7, 4G6, 7Dl2, 7Cl, 7H2, 6A2 and 6Cl, is provided in APPENDIX A. Applicant argues that this alignment shows a substantially high degree of similarity between sequences, including the CDRs, of the claimed
polypeptides. Applicant argues that the claimed polypeptides share a single structural similarity. Applicant argues that the polypeptides of Claim 167 each share a common use that flows from the substantial structural feature, specifically, to bind ILlRAP. Applicant argues that such polypeptides that bind ILlRAP would have applications, for example, in the detection of ILlRAP; targeting of ILlRAP with chimeric antigen receptor proteins (CARs) or with conjugated drugs; and treatment of ILlRAP-expressing cancer
cells.
Applicant argues that each of clones 7Cl (e.g., SEQ ID NO:160), 7H2 (e.g., SEQ ID NO:168), 6A2 (e.g., SEQ ID NO:176) and 6Cl (e.g., SEQ ID NO:184) were each derived from either clones 3A7 or 4G6. A Declaration of Dr. H. Zhang confirms that "the binders 7Dl2, 7Cl and 7H2 were derived from clone 3A7 and binders 6A2 and 6Cl were derived from clone 4G6 by affinity maturation using an error-prone PCR-based phage library evolution strategy combined with kinetic (koff) panning." Applicant argues that
Dr. Zhang also confirms that clones 7Cl, 7H2, 6A2 and 6Cl each bind IL1RAP. In addition, Applicant argues that the binding of IL1RAP by each of the claimed polypeptides would have been reasonably predicted from the substantially high degree of similarity between sequences, including the CDRs, of the claimed polypeptides, and the showing that at least 3A7, 4G6 and 7Dl2 bound recombinant IL1RAP. Applicant argues that that each of the polypeptides of Claim 167 share the common function of binding IL1RAP, which would have been readily understood by the skilled person to have flowed from substantially similar structural features, such as the high degree of
similarity between sequences of the claimed polypeptides. Applicant argues that each of 3A7, 4G6 and 7Dl2 were shown to bind recombinant IL1RAP when expressed as recombinant immunoglobulins. Applicants argue that despite any minor differences between certain sequences of the claimed polypeptides, each of the polypeptides of Claim 167 would be understood by the skilled person to have retained antigen-binding
activity.
Applicant also argues that because all of the claimed polypeptides are single domain antibodies that bind to ILlRAP, they all share common functional properties such as having a smaller size than conventional antibodies, which may allow the antibodies to better penetrate solid tumors and provide other potential benefits over a full-length antibody such as lower immunogenicity, increased resistance to aggregation, more cost-effective production, the ability to target epitopes that cannot be accessed by full-size antibodies, lower toxicity and faster imaging when used as bioimaging reagents due to fast clearance, and an increased amenability to being engineered into other formats such as antibody-drug conjugates due to the reduced number of domains present.
Applicant’s arguments have been considered but are not persuasive. As an initial note, the number of combination from each subset of polypeptides form claim 167 would yield over 59,000 polypeptides. It is highly unlikely that mixing and matching all these various CDRs would result in polypeptides that bind the same epitope as the parent polypeptide. It is not clear which of these 59,000 combination would yield polypeptides capable of binding the same epitope as the elected polypeptide.
Furthermore, as previously discussed, the specification disclose that identified binding moieties included· 3A7, 4G6, and 3C5. The specification disclose that 3A7 and 4G6 were tested using wild-type and IL1RAP knock out cells and exhibited binding to the wild-type cells (Figure 25). However, it is not clear if the different anti-IR1 RAP antibodies 3A7n 4G6 3C5 bind to the same epitope. If the different antibodies bind to distinct epitopes there would not be a correlation between structure and function for the whole genus. The Court has indicated in Amgen Inc vs Sanofi ( 2017-1480, Fed Cir, 2017) that the disclosure of a well characterized antigen is insufficient for an adequate written description of the antibody that binds the antigen. Thus, antibodies that bind a specific antigen but having distinct amino acid sequences are not obvious variants of antibodies that bind the same antigen but having completely distinct amino acid sequences, especially given that the epitopes that the antibodies bind are distinct. For the different polypeptides it appears as if there is not a structurally function relationship in that the anti-il1RAP bind to completely different epitopes.
The specification discloses that nucleic acids encoding CARs were constructed: R.H04 CAR contained the 3A7 binding moiety; RJ105 CAR contained the 4G6 binding moiety; RJ106 CAR contained the 3C5 binding moiety; and RJ107 CAR contained the 7D12 binding moiety (Example 1). Thus, the specification does not disclose whether antibodies with the various substitutions within the different CDRs and various combinations of CDRs are capable of binding IL1RAP and capable of ameliorating or inhibiting an IL1RAP+ cancer in a subject.
Lastly, while the claims recite “a polypeptide capable of specifically binding an
IL1RAP” this is not an art-recognized class of molecules as defined in MPEP 2117 as: that it was known within the art that each member could be substituted one for the other, with the expectation that the same intended result would be achieved. In the instant case, the structurally different antibodies are not art-recognized substitutions for each other.
35 USC § 112(a) rejections maintained
The rejections of claims 167, 169-175 and 177-189 under 35 U.S.C. 112(a), as failing to comply with the written description requirement are maintained.
Applicant argues that amended Claim 167 relates to single domain antibodies, each comprising a heavy chain variable region with explicit amino acid sequences for a CDR1, CDR2 and CDR3, with an order that is implicit in a recited amino acid sequence related to SEQ ID NOs: 01, 02, 04, 160, 168, 176 or 184, as recited in Claim 167. Aspects of Claim 167 relate to clones (i) 3A7; (ii) 4G6; (iii) 7Dl2; (iv) 7Cl; (v) 7H2; (vi) 6A2; and (vii) 6Cl. With regard to clones (i)-(vii), the specification discloses each is a variable heavy (VH) domain, with a specific amino acid sequence which encompasses specific amino acid sequences for CDR1, CDR2 and CDR3 regions, and framework regions. Paragraph [0076] discloses that "antibody domain" can include an antibody such as a heavy chain variable domain (VH domain) in the absence of one or more other domains of an antibody; a single antibody domain having the ability to bind an antigen with CDRs, such as those listed in TABLE 15. Applicant argues that at least 3A7 and 4G6 were obtained by screening an expression library for binding to ILlRAP; and at least 7D12 was obtained by screening a secondary library derived from 3A7.
Each of 3A7, 4G6 and 7Dl2 bound recombinant ILlRAP when expressed as recombinant immunoglobulins. Chimeric antigen receptors (CARs) containing either 3A7 (RJ104 CAR); 4G6 (RJ105); or 7Dl2 (RJ107) had activity in a CAR-T cell lysis assay including at higher E:T ratios. At least CAR T cells containing CARs with either 3A7 (RJ104 CAR) or 7Dl2 (RJ107) had activity to induce cytokine expression against target cells. Applicant argues that an alignment of amino acid sequences for the clones readily shows a substantially high degree of similarity between the sequences. In
particular, 3A7, 7Dl2, 7H2 and 7Cl, each have the same CDR1 sequences, one clone has a single substitution in CDR2, and another clone has a single substitution in CDR3. For 4G6, 6A2 and 6Cl, one clone has a single substitution in CDR1, another clone has a single substitution in CDR2, and each has the same CDR3 sequence.
In addition, Dr. Zhang declares that "the binders 7Dl2, 7Cl and 7H2 were derived from clone 3A7 and binders 6A2 and 6C1 were derived from clone 4G6 by affinity maturation using an error-prone PCR-based phage library evolution strategy combined with kinetic (koff) panning." Such an affinity maturation strategy is an accepted methodology for enriching and selecting for antibodies that bind to a specific target. Moreover, Dr. Zhang also confirms that clones 7C1, 7H2, 6A2 and 6C1 each bind IL1RAP. Applciant argue that in view of at least the disclosure of methods to obtain the 3A7, 4G6 and 7Dl2 VH domain clones, their activities to bind IL1RAP, their activities in the context of a CAR, and the substantially high degree of similarity between the amino acid sequences for 3A 7, 4G6 and 7D 12, and the 7Cl, 7H2, 6A2 and 6C1 VH domain clones, including their CDR sequences, Applicant argues that a person of ordinary skill in the art in view of the instant application would readily and reasonably understand that Applicant was in full possession of the claimed polypeptides capable of binding IL1RAP and treating an IL1RAP+ cancer.
Applicant further argue that a person of ordinary skill in the art would readily recognize and understand that certain CDR sequences disclosed in TABLE 2 and
figure 10A relate to sequences according to the Chothia numbering system as shown in figure 10A, whereas the claimed CDRs for the elected binder 7D12, i.e. SEQ ID NOS:217-219, correspond to the CDRs numbered according to the Kabat numbering system. It is argued that it would be clear to a person skilled in the art who is familiar with both numbering systems that in particular the longer sequence for CDR2 given in Figure 10B corresponds to the generally longer region defined by sequence hypervariability by the Kabat numbering system, as contrasted with the generally shorter, structurally-based loop used to define CDR2 according to the Chothia
numbering system. The specification discloses activities of the 7Dl2 VH.
Applicant argues that a person of ordinary skill in the art would readily recognize and understand that certain CDR sequences disclosed in TABLE 2 and figure 10A relate to sequences according to the Chothia numbering system as shown in figure 10A, whereas the claimed CDRs for the elected binder 7Dl2, i.e. SEQ ID NOS:217-219, correspond to the CDRs numbered according to the Kabat numbering system. Applicant argues that it would be clear to a person skilled in the art who is familiar with both numbering systems that in particular the longer sequence for CDR2 given in Figure 10B corresponds to the generally longer region defined by sequence hypervariability by the Kabat numbering system, as contrasted with the generally shorter, structurally-based loop used to define CDR2 according to the Chothia numbering system. As indicated above, the specification discloses activities of the 7Dl2 VH domain which would have included a CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NO:217, 218, and 219, respectively.
Applicant argues that a person skilled in the art would understand from the specification as filed that the seven presently claimed single domain antibodies could be used to ameliorate or inhibit an IL1RAP+ cancer in a subject. Applicant argues that the present specification establishes a recognized scientific basis for targeting ILlRAP in cancer therapy. For example, paragraph [0295] of the specification confirms that IL1RAP is expressed on the cell surface in some cancers and is thus a therapeutic
target for such cancer cells. Applicant further argues that the data provided in the specification establish that certain identified binders when incorporated into a CAR construct can be used to target the CAR-T containing cells to IL1RAP+ cancer cells in vitro to trigger lysis of those cancer cells, and similarly the specification provides support for using these binders in a recognized antibody-drug conjugate format to similarly target and kill IL1RAP+ cancer cells. Applicant argues that the person skilled in the art would understand from the specification as filed that the administration of a CAR-T containing cell or an antibody-drug conjugate incorporating the claimed single domain antibodies as a targeting agent would be likely to ameliorate or inhibit an IL1RAP+ cancer by killing IL1RAP+ cancer cells.
Applicant’s arguments have been considered but are not persuasive. Claim 67 section (iii) are drawn to a polypeptide comprising a single domain antibody capable of specifically binding an interleukin-I receptor accessory protein (IL1RAP), comprising a heavy chain variable domain or region comprising: a CDR1 having the amino acid sequence set forth in one of SEQ ID NOs:217 or 314-323, a CDR2 having the amino acid sequence set forth in one of SEQ ID NOs:218 or 324-333, and a CDR3 having the amino acid sequence set forth in one of SEQ ID NOs:219 or 334-343 and comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEO ID NO:04; and methods of treating, ameliorating or inhibiting an ILIRAP+ cancer in a subject.
The sequences for SEQ ID NOs: 219 and 334-343 are below
Trp Gly Ala Gly Lys Asp Val
Trp Ser Ala Gly Lys Asp Val
Trp Gly Ala Ser Lys Asp Val
Trp Gly Ala Gly Lys Asp Leu
Trp Gly Thr Gly Lys Asp Val
Trp Gly Ala Gly Lys Glu Val
Trp Gly Ala Gly Lys Glu Leu
Trp Thr Ala Gly Lys Glu Val
Trp Gly Ala Thr Lys Asp Leu
Trp Gly Ala Thr Lys Glu Val
Trp Gly Ala Gly Lys Asp Ala
Thus, the sequences for the HCDR3 of SEQ ID NOs: 334-343 differ by one amino acid from SEQ ID NO:219 and two amino acids from each other. The number of combinations from subset (iii) of polypeptides form claim 167 would yield over 59,000 polypeptides. It is highly unlikely that mixing and matching all these various CDRs would result in polypeptides that bind the same epitope as the parent polypeptide. Claim 167 encompasses over 413,000 polypeptides. It would be impossible to know which of these polypeptides would bind the same epitope as the parent polypeptide only knowing the amino acid sequence of the CDRs of the polypeptides. As stated previously, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982, cited previously). Rudikoff teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al (Biochemical and Biophysical Research Communications, 2003, Vol. 307, pp. 198-205, IDS), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDRH3 is at the center of most if not all antigen interactions, other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
It is not clear how many of the claimed 59,000 polypeptides would bind to the same epitope as the single domain antibody comprising a heavy chain variable domain or region comprising: a CDR1 having the amino acid sequence set forth in SEQ ID NOs:217, a CDR2 having the amino acid sequence set forth in SEQ ID NOs:218 and a CDR3 having the amino acid sequence set forth in one of SEQ ID NOs:219 let alone how many of 59,000 polypeptides are capable of binding IL1RAP. It is also not clear how many of the claimed 59,000 polypeptides would be capable capable of ameliorating or inhibiting an ILlRAP+ cancer in a subject.
In response to Applicant’s argument that the data provided in the specification establish that certain identified binders when incorporated into a CAR construct can be used to target the CAR-T containing cells to IL1RAP+ cancer cells in vitro to trigger lysis of those cancer cells, the specification only appears to disclose two cell lines RJ104 and RJ107 comprising anti-IL1RAP antibodies capable of binding IL-1RAP having relatively high cytotoxic activity against the AML cell lines. The specification discloses that nucleic acids encoding CARs were constructed: R.H04 CAR contained the 3A7 binding moiety; RJ105 CAR contained the 4G6 binding moiety; RJ106 CAR contained the 3C5 binding moiety; and RJ107 CAR contained the 7D12 binding moiety (Example 1). The specification disclose that cells containing either the RJ104 CAR or RJ107 CAR readily lysed target TC71 cells at lower E:T ratios. In contrast, T cells containing either the RJ105 CAR or RJ106 CAR did not readily lyse target TC71 cells at lower E:T ratios (Example 3). The specification does not disclose that any of the CARs was capable of ameliorating or inhibiting an ILlRAP+ cancer in a subject. It is not clear from the Examples whether RJ105 CAR or RJ106 CAR would be capable of ameliorating or inhibiting an ILlRAP+ cancer in a subject. Furthermore, the specification does not disclose whether CARs comprising the single chain antibodies with the various substitutions within the different CDRs and various combinations of CDRs were capable of binding IL1RAP and ameliorating or inhibiting an ILlRAP+ cancer in a subject.
In addition, the specification does not appear to disclose that single chain antibodies alone were capable of binding IL1RAP and ameliorating or inhibiting an IL1RAP+ cancer in a subject.
In response to Dr Zhang’s disclosure that establishing that IL1RAP-targeting antibody-drug conjugates incorporating the claimed 7D12 single domain antibody are effective in killing multiple cancer cell lines expressing IL1RAP in vitro and further were effective in an in vivo experiment to block tumor growth and cause rapid regression of established tumors expressing IL1RAP, the only conjugated antibody in the claims was an anti-conjugated to a radioisotope. It appears that the single domain antibodies were conjugated to the topoisomerase l inhibitor DXd in the manuscript submitted by Dr Zhang. It is not clear whether the claimed single domain antibodies conjugated with a radioisotope or any antibody-drug conjugate were capable of ameliorating or inhibiting an ILlRAP+ cancer in a subject. Furthermore, it is not clear which of the numerous conjugated single chain antibodies with the various combinations of CDRs in section (iii) would be capable of ameliorating or inhibiting an ILlRAP+ cancer in a subject.
Thus, the specification does not provide an adequate written description of the claimed genus of antibodies in section (iii) with various combinations of CDRs would be capable of specifically binding to IL1RAP. The specification does not provide an adequate written description of the claimed genus of antibodies in section (iii) which specifically binds to IL1RAP would be capable of ameliorating or inhibiting an ILlRAP+ cancer in a subject.
The Court in Amgen Inc vs Sanofi ( 2017-1480, Fed Cir, 2017) stated “an adequate written description must contain enough information about the actual makeup of the claim products – a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material,” which may be present in “function “terminology “ when the art has established a correlation between structure and function” (page 17, 1st paragraph).
Applicants have not described the genus of anti- IL1RAP antibodies sufficiently to show they had possession of the claimed genus. Since the disclosure fails to provide sufficient relevant identifying characteristics, and because the genus is highly variant, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Summary
Claims 167, 169-175 and 177-189 stand rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MARK HALVORSON/Primary Examiner, Art Unit 1646