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 .
Status of Claims
Claims 1-20, 22 and 26 are pending.
Claims 3, 4, 6, 8, 11-16, 18-20, 22 and 26 have been amended.
Claims 1-20, 22 and 26 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The U.S. effective filing date of all claims under examination is set at 08/20/2021 based on the EP21192286.9 application (filed on 08/20/2021).
Information Disclosure Statement
The information disclosure statement (IDS) submitted is being considered by the examiner.
Claim Objections
Claims 1, 11, 12, 16-18 and 26 are objected to because of the following informalities:
Claim 1 appears to contain a typographical error. The word “region” should be amended to the plural “regions” to describe the CDR1, CDR2 and CDR3 regions.
Claims 11, 12, 16-18 and 26 would be in better form if the claims were amended to include the indefinite article “A” at the beginning of each of the sentences. For claim 11 the claim would recite “A [[C]]conjugate comprising….”; claim 12 would recite “A [[P]]pharmaceutical composition…..”; claim 16 would recite “A [[N]]nucleic acid molecule…..”; claim 17 would recite “An [[E]]expression vector…..”; claim 18 would recite “A [[H]]host cell…..”; and claim 26 would recite “A [[K]]kit for detecting…..”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20, 22 and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the CDR1, CDR2 and CDR3 region of a VHH domain of a camelid heavy chain antibody”. There is insufficient antecedent basis for “the CDR1, CDR2 and CDR3 region” in the claim. Since all claims depend on claim 1, dependent claims 2-20, 22 and 26 are also rejected here.
Claim 20 recites “the detection and/or purification and/or concentration of CD73 and/or CD73-expressing cells in a biological sample”. There is insufficient antecedent basis for “the detection and/or purification and/or concentration of CD73 and/or CD73-expressing cells in a biological sample” in the claim.
Claim 22 recites the limitation "the diagnosis of a disease characterised by increased CD73 expression”. There is insufficient antecedent basis for "the diagnosis of a disease characterised by increased CD73 expression” in the claim.
Claim Rejections 35 U.S.C.112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 4, 5, 7, 9 and 10 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.
In the instant case, the following genus of: antigen-binding polypeptides comprising the CDR1, CDR2 and CDR3 region of a VHH domain of a camelid heavy chain antibody, characterised in that the polypeptide specifically binds to CD73, have been noted:-
claim 4 is inclusive of a genus of antigen-binding polypeptides comprising the CDR sequences shown in instant SEQ ID NO:1-3, wherein there are a total of thirteen “X” residues among the three CDRs, and each “X” has two or three possible amino acid residue options; and wherein there is one “I” residue in CDR2 which has two possible amino acid residue options; this amounts to a total of 589824 possible sets of CDR combinations responsible for providing the function of binding to CD73;
claim 5 is inclusive of a genus of antigen-binding polypeptides comprising recited CDR combinations (a) to (h) that can have one amino acid mutation per CDR region, wherein there are 9 residues in CDR1, 7 residues in CDR2 and 15 residues in CDR3; this amounts to a total of 8 x 10 x 8 x 16 = 10240 possible sets of CDR combinations responsible for providing the function of binding to CD73;
claim 7 is inclusive of a genus of antigen-binding polypeptides comprising recited CDR combinations (a) to (c) that can have one amino acid mutation per CDR region, wherein there are 9 residues in CDR1, 7 residues in CDR2 and 17 residues in CDR3; this amounts to a total of 3 x 10 x 8 x 18 = 4329 possible sets of CDR combinations responsible for providing the function of binding to CD73;
claim 9 is inclusive of a genus of antigen-binding polypeptides comprising recited CDR combinations (a) to (f) that can have one amino acid mutation per CDR region, wherein there are 9 residues in CDR1, 7 residues in CDR2 and 12 residues in CDR3; this amounts to a total of 6 x 10 x 8 x 13 = 6240 possible sets of CDR combinations responsible for providing the function of binding to CD73; and
claim 10 is inclusive of a genus of antigen-binding polypeptides comprising the amino acid sequence having at least 80% or more sequence identity to one of the amino acid sequences of SEQ ID NO:61-77; which includes mutations of up to 20% in and around the CDR regions responsible for providing the function of binding to CD73.
However, the written description in this case only sets forth:
six clones, namely clones SB96, SB142, SB116, SB144, SB121 and SB139, disclosed in Table 1 (Pg 29-30 of instant specification);
nine clones, namely clones SB98, SB115, SB107, SB108, SB123, SB124, SB125, SB141 and SB143, disclosed in Table 2 (Pg 32 of instant specification);
one clone, namely SB167, disclosed in Example 9 (Pg 34 lines 17, 18 and 25); and
one clone, namely SB188, disclosed in Example 10 (Pg 34 lines 34 and 35 and Pg 35 lines 6 and 7),
which sets forth a total of seventeen clones of CD73-binding VHHs but without disclosing the full set of CDR1, CDR2 and CDR3 amino acid sequences for any of the clones, except for disclosing the CDR3s for clones SB96, SB142, SB116, SB144, SB121 and SB139 as disclosed in Table 1. Therefore, no complete set of CDR1, CDR2 and CDR3 of any CD73-binding VHH has been explicitly disclosed. The specification does not disclose, and the art does not teach, the genus of antigen-binding polypeptides comprising the CDR1, CDR2 and CDR3 region of a VHH domain of a camelid heavy chain antibody, characterised in that the polypeptide specifically binds to CD73 as broadly encompassed in the claims.
As is well-known in the antibody art at the time of filing, the specificity of an antibody is dependent upon the CDR regions and different combinations of CDR sequences greatly alter antigen binding. With respect to VHH antibodies, the VHH antibody-antigen binding domain functionality was known to depend on the entire structure, particularly a full complement of three CDRs. It is understood by one of ordinary skill in the art that uncharacterized CDR binding is unpredictable and that each construct requires function testing. Bever et al. (Anal Bioanal Chem (2016) 408:5985–6002) teaches VHH antibodies, and the production and screening thereof (Title and Abstract). Bever et al. teaches Nanobodies® are VHH domain antibodies that are heavy chain only (e.g. HcAb) that are naturally produced by camelids and sharks (Pg 5985, “Introduction”). Bever et al. teaches the overview of the process of making VHH antibodies wherein (1) an alpaca is the camelid species; (2) mRNA is collected from the alpaca and a cDNA library is constructed; (3) VHH genes are isolated; (4) a phage-display VHH library is generated; (5) solid phase panning is conducted to select the desired VHH; and (6) the desired VHH is obtained (Figure 2).
Hacisuleyman and Erman (Journal of Biological Physics (2020) 46:189–208) teaches VHH optimization (Title and Abstract). They teach VHH antibodies comprise 3 CDRs which determine target specificity, with CDR3 being the “dominating contributor in antigen recognition” (Pg. 191 and Fig. 2). Hacisuleyman and Erman further teaches residue numbers for the VHH CDRs may vary, and that in nature CDRs are mutated naturally to increase the binding affinity and specificity towards a target antigen (Pg. 191). In addition, Hacisuleyman and Erman teaches that computational screening methods for optimization are a first step that is then followed by experimental strategies (Pg. 191]). Hacisuleyman and Erman do not support de novo generation of VHH CDRs to bind a selected antibody, but rather requires the researcher start with a VHH antibody known to bind the target antigen (Pg. 191).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of species antigen binding polypeptides that encompass the genus nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of seventeen clones but without their full set of CDR1, CDR2 and CDR3 regions for binding to CD73 found in the specification is insufficient to describe the genus. Thus, 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.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections 35 U.S.C.112(a) – (Second)
Claims 4-10 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 antigen-binding polypeptides comprising VHH CDR1, CDR2 and CDR3 regions that are fully defined by every single amino acid and shown to have functional binding to CD73; does not reasonably provide enablement for antigen-binding polypeptides comprising VHH CDR1, CDR2 and CDR3 regions that have just any mutations which have not been tested for binding functionality. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The nature of the invention
Claim 4 is drawn to CD73-binding polypeptides comprising the CDR sequences shown in instant SEQ ID NO:1-3, wherein there are a total of thirteen “X” residues among the three CDRs, and each “X” has two or three possible amino acid residue options; and wherein there is one “I” residue in CDR2 which has two possible amino acid residue options; this amounts to a total of 589824 possible sets of CDR combinations responsible for providing the function of binding to CD73.
Claim 5 is drawn to CD73-binding polypeptides comprising recited CDR combinations (a) to (h) that can have not more than one amino acid mutation per CDR region, wherein there are 9 residues in CDR1, 7 residues in CDR2 and 15 residues in CDR3; this amounts to a total of 8 x 10 x 8 x 16 = 10240 possible sets of CDR combinations responsible for providing the function of binding to CD73.
Claim 6 is drawn to CD73-binding polypeptides comprising the CDR sequences shown in instant SEQ ID NO:28-30, wherein there are a total of four “X” residues among the three CDRs, and each “X” has two possible amino acid residue options; this amounts to a total of 16possible sets of CDR combinations responsible for providing the function of binding to CD73.
Claim 7 is drawn to CD73-binding polypeptides comprising recited CDR combinations (a) to (c) that can have not more than one amino acid mutation per CDR region, wherein there are 9 residues in CDR1, 7 residues in CDR2 and 17 residues in CDR3; this amounts to a total of 3 x 10 x 8 x 18 = 4329 possible sets of CDR combinations responsible for providing the function of binding to CD73.
Claim 9 is drawn to CD73-binding polypeptides comprising recited CDR combinations (a) to (f) that can have not more than one amino acid mutation per CDR region, wherein there are 9 residues in CDR1, 7 residues in CDR2 and 12 residues in CDR3; this amounts to a total of 6 x 10 x 8 x 13 = 6240 possible sets of CDR combinations responsible for providing the function of binding to CD73.
Claim 10 is drawn to CD73-binding polypeptides comprising the amino acid sequence having at least 80% or more sequence identity to one of the amino acid sequences of SEQ ID NO:61-77; which includes mutations of up to 20% in and around the CDR regions responsible for providing the function of binding to CD73.
The breadth of the claims
The claims are broad in that they encompass mutations in the CDRs of the CD73-binding polypeptide that would retain the function of binding to the target antigen.
The amount of direction provided by the inventor/the existence of working examples
The specification discloses a total of seventeen clones, namely clones SB96, SB142, SB116, SB144, SB121 and SB139, disclosed in Table 1 (Pg 29-30 of instant specification); clones SB98, SB115, SB107, SB108, SB123, SB124, SB125, SB141 and SB143, disclosed in Table 2 (Pg 32 of instant specification); clone SB167, disclosed in Example 9 (Pg 34 lines 17, 18 and 25); and clone SB188, disclosed in Example 10 (Pg 34 lines 34 and 35 and Pg 35 lines 6 and 7), which sets forth a total of seventeen clones of CD73-binding VHHs but without disclosing the full set of CDR1, CDR2 and CDR3 amino acid sequences for any of the clones, except for disclosing the CDR3s for clones SB96, SB142, SB116, SB144, SB121 and SB139 as disclosed in Table 1. Therefore, no complete set of CDR1, CDR2 and CDR3 of any CD73-binding VHH has been explicitly disclosed.
Therefore, the disclosure does not discuss, or demonstrate through working examples, any novel mutants of the CD73-binding VHH, that retain the instant claimed functionalities.
The state of the art/the level of predictability in the art
The state of the art teaches that with regards to changes in the amino acid residues on antigen-binding polypeptides, it is especially important to disclose which residues are permissive to mutation. With respect to VHH antibodies, at the time of filling, the VHH antibody-antigen binding domain functionality was known to depend on the entire structure, particularly a full complement of three CDRs. It is understood by one of ordinary skill in the art that uncharacterized CDR binding is unpredictable and that each construct requires function testing. Bever et al. (Anal Bioanal Chem (2016) 408:5985–6002) teaches VHH antibodies, and the production and screening thereof (Title and Abstract). Bever et al. teaches Nanobodies® are VHH domain antibodies that are heavy chain only (e.g. HcAb) that are naturally produced by camelids and sharks (Pg 5985, “Introduction”). Bever et al. teaches the overview of the process of making VHH antibodies wherein (1) an alpaca is the camelid species; (2) mRNA is collected from the alpaca and a cDNA library is constructed; (3) VHH genes are isolated; (4) a phage-display VHH library is generated; (5) solid phase panning is conducted to select the desired VHH; and (6) the desired VHH is obtained (Figure 2).
Hacisuleyman and Erman (Journal of Biological Physics (2020) 46:189–208) teaches VHH optimization (Title and Abstract). They teach VHH antibodies comprise 3 CDRs which determine target specificity, with CDR3 being the “dominating contributor in antigen recognition” (Pg. 191 and Fig. 2). Hacisuleyman and Erman further teaches residue numbers for the VHH CDRs may vary, and that in nature CDRs are mutated naturally to increase the binding affinity and specificity towards a target antigen (Pg. 191). In addition, Hacisuleyman and Erman teaches that computational screening methods for optimization are a first step that is then followed by experimental strategies (Pg. 191]). Hacisuleyman and Erman do not support de novo generation of VHH CDRs to bind a selected antibody, but rather requires the researcher start with a VHH antibody known to bind the target antigen (Pg. 191).
Further, an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Not knowing and absent further experimentation, which modifications can retain CD73 binding function and which cannot, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict or otherwise envisage all possible mutations in the CDR regions of the VHH comprising the recited amino acid sequences encompassed in the claims that would retain the binding function to CD73. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to function test all possible mutations on the CD73-binding polypeptides for retention of functional activity.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. This is because the art teaches that it is unpredictable whether or not CDR variants of known antibodies or binding polypeptides will function as such, and the specification does not provide direction on which constructs below 100% identity have function, or do not have function, as claimed in order to perform the method as claimed. In other words, the specification does nothing to ameliorate these concerns over the breadth of the claims rejected above with respect to functional variants, therefore, one would be burdened with undue experimentation to make or use the products of instant claims as broadly as they are currently claimed.
Enablement can be met by amending the claims to recite the CDR region amino acid sequences without any variations.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 11-20, 22 and 26 are rejected under 35 U.S.C. 103(a) as being unpatentable over Cremasco et al. (WO2018237173A1 Date Published 2018-12-27) in view of Minter et al. (WO2016075099A1 Date Published 2016-05-19) and Bannas et al. (Front Immunol, Volume 8: 2017; Pg 1-13).
Cremasco co et al. teaches anti-CD73 antibody molecules and therapies using the same for treating cancer (Abstract and Pg 8-9). They teach that the anti-human CD73 antibody MEDI9447 can inhibit tumor growth (WO2016/075099 incorporated by reference in its entirety; Pg 8 second paragraph and Pg 43 fifth paragraph, lines 1-6). Cremasco et al. teaches CD73-binding antibody molecules can optionally have the format of naturally occurring single domain antibodies (VHH) derived from camelid (Pg 25 to Pg 26 paragraph spanning and Pg 120 first paragraph line 6).
Cremasco et al. does not specifically teach making a CD73-binding polypeptide comprising CDR1, CDR2 and CDR3 regions of a VHH domain of a camelid heavy chain antibody; or a conjugate, or a pharmaceutical composition, or a kit comprising said VHH domain; or a host cell comprising a nucleic acid molecule comprising said VHH domain; or methods for producing and using said VHH domain.
However, these deficiencies are made up in the teachings of Minter et al and Bannas et al.
Minter et al. (WO2016/075099) teaches anti-CD73 antibodies conjugated to cytotoxic agents, polynucleotides encoding said antibody, vectors comprising said polynucleotides, host cells comprising said polynucleotides, as well as pharmaceutical compositions and kits comprising said anti-CD73 antibody or antigen binding fragment thereof (paragraphs [00393], [00169], [00380] and [00479]).
Minter et al. also teaches a method of treating a disease involving administering a therapeutically effective amount of an anti-CD73, such as MEDI9447, to a subject identified as having a tumor that has increased expression of CD73 compared to a reference; wherein the tumors include colon cancer, melanoma, breast cancer, lymphoma, non-small cell lung carcinoma, ovarian cancer, breast cancer, head and neck cancers, pancreatic cancer , and Burkitt's lymphoma (paragraphs [0034], [0040] and [0180]).
Minter et al. further teaches a method of making a CD73-binding antibody or antigen-binding fragment thereof, involving culturing host cells comprising the nucleic acid sequence of said antibody, and purifying the antibody or antigen-binding fragment thereof (paragraphs [0030] and [00423] to [00426]). They teach a method for detecting CD73 protein expression of biological specimens or samples by applying a labeled CD73-antibody or antigen-binding fragment to said sample and detecting the signal of the label that is in complex with CD73 expressed in the sample (paragraphs [00481] and [00507]). They also teach diagnostic methods for diagnosis of CD73-expressing cell-mediated diseases comprising measuring the expression level of CD73 protein in tissues from an individual and comparing the measured expression level with a standard CD73 expression level in normal tissue, whereby an increase in the expression level compared to the standard is indicative of a disorder (paragraph [00475]). They further teach that anti-CD73 antibody MEDI9447 can be used to assay CD73 protein levels in a biological sample using classical known immunohistological methods including ELISA, immunoprecipitation, or Western blotting (paragraph [00476]).
Bannas et al. teaches that camelids naturally produce antibodies composed only of heavy chains in which the target recognition module is composed of a single variable domain (VHH) or a nanobody (Nb) comprising three CDRs for antigen-binding (Abstract and Figures 1 and 2). They teach that VHH/Nb (15 kDa) and Nb-based human heavy chain antibodies (75 kDa) have high solubility and high stability as well as have advantageous features compared to full monoclonal antibodies due to their small size and good tumor penetration in vivo (Abstract and Pg 5 right column second paragraph lines 5-7). They also teach that VHH domains can readily be cloned into various formats by fusion to other proteins or effector domains, or conjugated to therapeutic agents, thereby tailoring their utility for specific therapeutic applications (Abstract, Pg 5 right column second paragraph lines 7-9 and Figure 6).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a VHH CD73-binding antibody molecule as taught by Cremasco et al. using methods of Minter et al. wherein VH and VL antigen-binding domains are replaced with a VHH domain antibody as taught by Cremasco et al. and Bannas et al. because Bannas et al. teaches VHH domain have advantageous characteristics which include small size and good tumor penetration in vivo and the ease of modifying the VHH domain attached to other proteins or therapeutic agents for effective tumor cell targeting and anti-tumor activities. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Allowable Subject Matter
The VHH antigen-binding polypeptide comprising:
(1) the CDR sequences shown in SEQ ID NO:4-6;
(2) the CDR sequences shown in SEQ ID NO:7-9;
(3) the CDR sequences shown in SEQ ID NO:10-12;
(4) the CDR sequences shown in SEQ ID NO:13-15;
(5) the CDR sequences shown in SEQ ID NO:16-18;
(6) the CDR sequences shown in SEQ ID NO:19-21;
(7) the CDR sequences shown in SEQ ID NO:22-24;
(8) the CDR sequences shown in SEQ ID NO:25-27
(9) the CDR sequences shown in SEQ ID NO:31-33;
(10) the CDR sequences shown in SEQ ID NO:34-36;
(11) the CDR sequences shown in SEQ ID NO:37-39;
(12) the CDR sequences shown in SEQ ID NO:43-45;
(13) the CDR sequences shown in SEQ ID NO:46-48;
(14) the CDR sequences shown in SEQ ID NO:49-51;
(15) the CDR sequences shown in SEQ ID NO:52-54;
(16) the CDR sequences shown in SEQ ID NO:55-57; and
(17) the CDR sequences shown in SEQ ID NO:58-60, are free of prior art.
In addition, VHH antigen-binding polypeptide comprising the amino acid sequences of SEQ ID NO:61-77 are free of prior art.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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