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 .
Applicant’s remarks, filed 8/4/2026, are acknowledged and entered into the record. Applicants amended claims 1, 3-4, 6-8, 15-21 and 34, canceled claim 14, and added new claim 35 in the remarks of 8/4/2026.
Priority- Foreign
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(a)-(d) and (f) or under 35 U.S.C. 120, 121, 365(a) or (b), or 386(a) is acknowledged. The present application is drawn from PCT/EP2022/052919, filed 2/7/2022; and claims benefit under 35 U.S.C. (119(a)-(d) to foreign applications PCT/EP2021/052885, filed 2/5/2021; EP 21166835.5, filed 4/2/2021; and EP 21173680.6, filed 5/12/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-11, 14-22, 25 and 32-33, in the reply filed on 4/9/2026 is acknowledged. Claims 26-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups III and IV, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/9/2026.
Applicant’s election without traverse of the species of binding agent comprising the CDRs 1-3 of SEQ ID NOs: 9, 14 and 15, respectively; and the FRs 1-4 of SEQ ID NOs: 21, 18, 24 and 28, respectively, in the reply filed on 4/9/2026 is acknowledged. Applicants canceled claims 23-24, and added new claim 34 in the remarks of 4/9/2026, and new claim 35 in the remarks of 8/4/2026. Claims 1-11, 14-16, 22, 25 and 32-34 read on the elected species. Claims 17-21 are withdrawn as not reading on the elected species. Specifically, none of the binding agents of SEQ ID NOs: 1-5, 53-55 or 59 comprise the CDRs 1-3 of SEQ ID NOs: 9, 14 and 15, respectively and the FRs 1-4 of SEQ ID NOs: 21, 18, 24 and 28, respectively.
Status of Claims
Claims 1-11, 14-22, 25-35 are pending; claims 17-21 and 26-31 are withdrawn; claims 1-11, 15, 16, 22, 25 and 32-35 are being examined on the merits.
Claim Objections
The claim objections of 5/5/2026 are withdrawn. Applicants amended the claims to resolve the objections.
Claim Rejections – Maintained
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.
Claims 1-11, 22, 25 and 32-35 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 a binding agent, wherein the ISVD or functional part thereof “comprises the CDRs present in any of SEQ ID NOs: 1 to 5 and 59 or SEQ ID NOs: 53-55, wherein the CDRs are annotated according to Kabat, MacCallum, IMGT, AbM, or Chothia.” However, it is known in the art that various numbering schemes define the CDRs of an antigen binding domain differently. The specifications describe this scenario in Figure 42. For example, the CDR1 of VHH3.117 is defined according to Chothia as GKAVSIS, whereas it is defined by Kabat as ISDMG. Thus it is unclear what the minimum required sequence of the CDR1 is. Claim 1 does not claim the antibody by the full VHH; if this were the case, the necessary residues of the CDRs are necessarily present regardless of which number scheme is applied. Instead, claim 1 attempts to limit the claimed antibody solely by the CDRs of the full VHH sequences; therefore the CDR residues must be explicitly defined. Further, the CDRs cannot be described as “present” in any one of, for example, SEQ ID NOs: 1-5, as this can be interpreted as any random string of amino acid residues, of any length, at any location within the sequence, being described as a functional CDR domain. The skilled artisan, attempting to determine the limitations of the claim, must know what residues of the full VHH constitute the necessary and required CDRs that meet the limitations of the claims. As different numbering schemes are known in the art, and the different numbering schemes, applied to the various VHH sequences listed in the claims, would result in different amino acid sequences that define the same limitation, it is unclear what the necessary structural limitations of the antibody, or polynucleotide encoding an antibody, of the claims are.
Further, amended claim 1 recites CDRs of SEQ ID NO: 59. However, SEQ ID NO: 59 comprises “X” residues in the approximate region of the CDR3 domain. Claim 1 does not recite the various alternative amino acids that may be in the “X” residue. Thus it is unclear a) what residues “X” stands for, and b) whether the CDR definition would include the “X” residues or not. For example, Chothia defines the CDR3 of VHH 3.117 has comprising the amino acids GME at positions 109-111 of the VHH sequence; whereas IMGT does not include GME as part of the CDR3 at all (see Fig. 42). SEQ ID NO: 59 lists residues 109-111 of the VHH as G”X”E. Thus, what amino acid residue is “X109”, is it part of the CDR3 or the FR4, and would changing the amino acid residue at this position change how the CDR3 is defined across the different numbering schemes? Claim 16 depends from claim 1 and further limits the binding agents by framework (FR) regions, however it is necessary to know what the CDR domains are for the artisan to incorporate the required FR sequences to the construct. Here it is unclear what regions of the cited sequences the applicant considers as a CDR for use in the invention. As it is unclear what constitutes the corresponding “set” of 3 CDRs of the ISVD, or what amino acid residues define any particular CDR, it is unclear what the necessary requirements of the CDRs of the invention are. As the metes and bounds of the claims are unclear, claim 1 is rejected for indefiniteness. As claims 2-11, 22, 25 and 32-35 depend from claim 1, but fail to rectify the issue of indefiniteness, they are also rejected.
Response to Arguments
Applicant's arguments filed 8/4/2026 have been fully considered but they are not persuasive. Applicants amendments to the claims resolved the indefiniteness issue regarding whether the CDRs are to be selected from a single full embodiment, as a corresponding set, or whether the CDRs 1-3 may each be selectively chosen from the referenced full construct and put together. Applicant’s amendments make clear the latter, that each CDR is individually selected from the sequences of full constructs. This raises issues of adequate descriptive support for such a strategy (addressed below), but obviates indefiniteness as to what is being claimed. However, the rejection for indefiniteness also related to the lack of explicitly defined CDRs of claim 1, and of undefined “X” residues of, now canceled, claim 14, which are now present in amended claim 1, as SEQ ID NO: 59. The applicant has not addressed these issues of indefiniteness. The amino acid sequences of the CDRs of the VHHs (i.e. ISVDs) should be explicitly defined for each claimed embodiment of the claimed VHH, such that there is no question to the skilled artisan as to what the CDRs of the claimed ISVDs are required to be, and what the necessary limitations of the claim are. Here the applicants provide several different full constructs, suggest that the CDRs in each construct may be differentially defined by various numbering schemes, that any of the variously defined CDRs may be individually selected, and wherein some CDRs have undefined X residues. This includes the elected species, which itself is not embodied in any of the full constructs of claim 1. Taken together, the claim has too many inter-related yet variable limitations for the artisan to have a clear idea of what the necessary structural limitations of the ISVDs, or their functional part thereof, are. Thus the CDR sequences are not explicitly defined, rather they are open to various interpretations, and therefore are unclear. Applicants have not addressed all indefinite issues of claim 1; therefore the rejections for indefiniteness are maintained.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-11, 15, 16, 22, 25 and 32-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claim 1 recites a sarbecovirus binding agent that specifically binds to the spike protein receptor binding domain (SPRBD), yet still allows binding of ACE2 to the SPRBD, and is at least neutralizing towards SARS-CoV-2 and SARS-CoV-1; and wherein the binding agent comprises an ISVD or functional part thereof, wherein the ISVD comprises the CDRs present in any of SEQ ID NOs: 1-5 and 59, or 53-55, which are each a VHH construct (specs., pg. 37), comprising 3 corresponding CDRs. Thus, claim 1 is interpreted as ISVDs comprising any of various CDRs of SEQ ID NOs: 1-5, 53-55 and 59. Further, claim 1 recites whereby the CDRs of SEQ ID NOs: 1-5, 53-55 and 59 are defined by any of the Kabat, MacCallum, IMGT, AbM, or Chothia numbering schemes. Thus, claim 1 encompasses any of the CDRs of SEQ ID NOs: 1-5, 53-55 and 59, whereby each CDR is defined differentially across any of the various numbering schemes. Further, SEQ ID NO: 59 defines a CDR3 which comprise 2 “X” residues, which are undefined and presumed to be any amino acid residues, at each location, in any combination. Thus, the CDR3 of SEQ ID NO: 59, alone, encompasses 400 different embodiments. Thus, the broadest reasonable interpretation of claim 1 is to a genus of anti-SPRBD binding agent ISVDs comprising at least one CDR region selected from SEQ ID NOs: 1-5 and 59, or 53-55, and whereby the explicit amino acid sequences of the CDRs are alternately defined, and whereby the X residues are undefined; thus claim 1 is drawn to a vast number of ISVD alternatives. Claim 15, which depends from claim 1, further limits the ISVD to those comprising CDRs 1-3, whereby CDR1 may be from either of SEQ ID NO: 9 or 10, the CDR2 may be from either of SEQ ID NOs: 11-14, and CDR3 may be either of SEQ ID NOs: 15-16. Thus, claim 15 is drawn to at least 16 separate embodiments of ISVD, combined with all the alternative definitions of each CDR based on the selected numbering scheme, and whereby individual CDRs derived from one construct may be mixed and matched to generate alternative embodiments.
It is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). Further, it is known that the heavy chain CDR2 and CDR3 regions contain most of the residues that have a major contribution to the binding free energy of the antigen binding domain (Dondelinger et al., 2018; pg. 8, col. 1, para. 2 – col. 2, para. 1). Regarding single domain antibodies (sdAbs), which comprise only a VHH heavy chain, comprising the 3 heavy chain CDRs, Sheriff et al., (1998) teaches that while the usual conception is that an antibody (or receptor) envelops its ligand, with sdAbs derived from camels, the antibody inserts a part of its binding surface deeply into a pocket on the surface of the ligand; and that about 70% of the total surface area buried in this interaction is contributed by CDR3 (pg. 735, col. 2, para. 2 – col. 3, para. 1). Thus, the CDR3 of sdAbs is of considerable importance to the functionality of the sdAb with regard to specificity and affinity. However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1). Thus, while antibodies share certain characteristics such as Fc regions or hinge regions, these regions are not correlated with the binding function of the antibody. Conversely, the hyper-variable regions, comprising the complementary set of 6 CDRs (or 3 CDRs in the case of VHHs), are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Moreover, and regarding the properties of the ISVDs of claims 1-11, and new claim 35, the decision arrived at in Amgen v. Sanofi, 872, F.3d 1367 (Fed. Cir. 2017) supports expanded analysis of whether a claim drawn to an antibody being specific for an epitope, even a specific epitope, permits an applicant to pursue all possible antibodies that are capable of being produced against such an epitope. That is, “disclosure of an antigen fully characterized by its structure, formula or physical properties does not, without more, provide adequate written description of an antibody claimed by its binding affinity to that antigen” (Amgen v. Sanofi, 872, F.3d 1367 (Fed. Cir. 2014)). This is pertinent to claims 1-11 and 35, which recite the amino acid residues of the epitope of the SPRBD to which the binding agents bind. However, description of the points of contact, or binding affinity, of the binding agent do not inform the skilled artisan as to the structure of the claimed invention, only the desired functional properties of such structures.
In support of the claimed genus of ISVDs comprising variant combinations of CDRs 1-3, the specifications disclose 8 species; the VHHs of SEQ ID NOs: 1-5 and 53-55. The specifications describe structural similarity in the CDRs of SEQ ID NOs: 1-5 (see Figure 1). However, the examples do not teach or reduce to practice alternative embodiments whereby the ISVDs comprise different CDR sequences with “X” residues that are substituted with any of the 20 alternative 20 amino acids, or whereby the CDRs are selected from across SEQ ID NOs: 1-5 and 59, or across SEQ ID NOs: 53-55 and are mixed-and-matched in alternative ISVDs. That is, not one example of mixing CDRs from across SEQ ID NOs: 1-5 into a functional ISVD is described. Further, there is no single embodiment taught in the specifications that comprises the elected species of ISVD, comprising the CDRs 1-3 of SEQ ID NOs: 9, 14 and 15, respectively. The specifications describe SEQ ID NOs: 1-5 as alternate variants, with a similar structural base for the CDRs but comprising point mutations at specific amino acid residues, any of which may potentially de-functionalize the variant ISVD when randomly combined, as described in the art above. Further, the CDRs of the VHHs of SEQ ID NOs: 53-55 are significantly different from that of SEQ ID NOs: 1-5. Figure 42 shows a comparison of the amino acid sequences of VHH 3.117 (SEQ ID NO: 1) versus VHH 3.89 (SEQ ID NO: 53). For example, it is clear from Figure 42 that the CDR3 of SEQ ID NO: 1 is significantly different from that of SEQ ID NO: 53. Thus, the ISVDs derived from SEQ ID NOs: 1-5 are not a proper Markush grouping with the ISVDs derived from SEQ ID NOs: 53-55, as the two claimed genus(es) are structurally disparate. It is known in the art, and described above, that the corresponding CDRs of a binding protein coordinate to form the binding domain; thus it is not clear that mixing and matching CDRs derived from various functional constructs would result in a functional binding domain. This is further complicated when the critical CDR3 of SEQ ID NO: 59 comprises two undefined X residues, which may be any amino acid, and thus represents 400 alternative embodiments of the CDR3 alone, which is then supposed to be mixed and matched with any other CDR1 and/or CDR2 to form a functional binding domain. No representative examples are described to support such an approach.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any variants of the selected species, in which “X” residues mutations were made, or whereby CDRs 1-3 are mixed-and-matched between SEQ ID NOs: 1-5 and 59, or SEQ ID NOs: 53-55, which were reduced to practice; nor do they identify the shared structural properties of the CDR residues that would define the genus beyond the desired functionality. Currently the essential property of binding SPRBD while allowing biding of ACE2 to the SPRBD, are imparted by the single, specific set of CDR sequences that have been reduced to practice; that of the VHHs of SEQ ID NOs: 1-5 and 53-55. Specifically, the physical features (or amino acid residues encoding said features) of the genus of variant ISVDs, which impart the property of binding the defined epitopes of claims 1-11 should be disclosed, such that it is clear which CDR residues would be necessarily present in every species of the claimed genus, should be described. Such a description would allow the skilled artisan, attempting to mix-and-match CDRs derived from across SEQ ID NOs: 1-5 and 53-55, to envision which species would have the desired functionality when reduced to practice. Further, a description of the type and number of amino acids substitutions at “X” residues, and whereby the resulting binding agents retain the claimed epitope specificity, would be essential in determining the degree of variability that may be allotted in mutated amino acid residues. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary corresponding CDRs of any single ISVD variant, or the type of amino acid substitutions that may be made at any claimed “X” residue, which would define the shared structural properties of all species variants that fall within the scope of the genus, it may be that many of the claimed genus of ISVDs of claim 1 would not bind the desired epitopes of the SPRBD, and would not neutralize SARS-CoV-2 or SARS-CoV-1.
In view of this uncertainty and the lack of a representative number of examples to support possession of the claimed genus, claims 1 and 15 are rejected for lack of adequate written description support. Claims 2-11, 16, 22, 25 and 32-35 are also rejected as they are dependent on rejected claim 1.
Further, new claim 35 is drawn to undefined humanized variants of claim 34, and wherein the humanized variant is a functional orthologue of SEQ ID NOs 1-5, with an ISVD of any one of SEQ ID NOs: 57-61. All of SEQ ID NOs: 57-61 comprise undefined X residues in the CDR domains. As discussed above, applicants have not provided sufficient descriptive support that all of the 400+ various embodiments of each of SEQ ID NOs: 57-61 would maintain binding functionality. Instead applicants seem to be claiming the genus by their functionality and not their structure, whereby any “functional orthologue” is encompassed in the claims. This suffers from a lack of descriptive support for possession of the invention and adequate description of the necessary structure, and shared structural properties across all embodiments of the claimed genes, which impart the desired functionality.
“The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the problem to be solved while claiming all solutions to it and … cover any compound later actually invented and determined to fall within the claim’s functional boundaries- leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
Applicants have not described the claimed genus of “functional orthologues” of SEQ ID NOs 1-5, whereby X residues may be any alternative amino acid, and which maintains binding to the specified epitope of instant claim 1. Thus applicants fail to show they had possession of the claimed genus. Claim 35 is rejected for lack of adequate written description.
Response to Arguments
Applicant's arguments filed 8/4/2026 have been fully considered but they are not persuasive. Applicants contend that the claimed variants of two disclosed binders, VHH3.117 (SEQ ID NO: 1) and VHH 3.42 (SEQ ID NO: 4), are described (remarks, pg. 9). Applicants contend that the scope of claim 15 is described in that the CDRs are variants of one another, essentially encompassing 2 CDR1 embodiments, 4 CDR2 embodiments and 2 CDR3 embodiments, and that 5 embodiments were reduced to practice, of 16 possible combinations, and therefore a representative number of embodiments have been described to claim the genus (remarks, pg. 10). Thus, applicants contend that the CDRs have been more narrowly defined such that the genus has been narrowed to those ISVDs present within one family with limited structural variation (remarks, pg. 11, para 2).
The examiner relies on the art teachings that even a single amino acid substitution, especially within a CDR domain, can defunctionalize a binding construct, as the binding specificity and affinity are determined by the proper folding of the protein and the inter-dependent nature of the CDR domains. Applicants amended instant claim 1 to narrow the mixing and matching of CDRs across the two families, and instead requires mixing and matching CDRs within a family. It is noted that the CDR3 of the two families are structurally disparate, thus the two families do not represent a proper Markush grouping of ISVDs. Further, applicants added SEQ ID NO: 59 to Family 1, of claim 1, which comprises X residues which are undefined in the claim and presumed to be any of the 20 amino acids. Thus, applicants have not narrowed the scope of the genus of the Family 1 ISVDs of claim 1, they have broadened the scope. Applicants demonstrate 5 embodiments of the family of claim 1, out of 16 possible combinations as recited in claim 15. However, applicants are demonstrating CDRs, of Family 1, which are defined by a specific kabat numbering scheme. Applicant’s arguments do not describe wherein each CDR is differentially defined across various numbering schemes, as claimed. Further, applicants show functionality of 5 specific combinations, and this does not account for alternative combinations, as claimed, which were not reduced to practice and shown to bind. If it is intended to be clear that the 5 specific embodiments work, why haven’t applicants generated embodiments of the other proposed combinations? The art suggests that such alternative combinations, may not work, and applicants have not reduced them to practice to demonstrate that they do. Applicants cite the specifications, pgs. 38-39, which describe the similarities of the CDR sequences, of Family 1, and which amino acids may be substituted at the specific residue locations to generate variants. The description of pages 38-39 is more narrow that what is claimed, as pgs. 38-39 define which residues can be varied and with which amino acids at each position. Nonetheless, applicants have not shown that any combination of CDRs will form a functional binding domain, but have shown that the 5 specific combinations do. That is only for Family 1. Applicants added SEQ ID NO: 59 to Family 1 of claim 1, which comprises undefined X residues, and thus significantly broadens the scope of the CDR sequences. Further, claim 1 recites the combinations of CDRs of Family 2; and wherein each of the CDRs of Family 2 may be differentially defined across various numbering schemes and mixed and matched. Applicants have not described any embodiments whereby the CDRs of Family 2 are mutated and/or mixed and matched, across SEQ ID NOs: 53-55, and whereby every combination results in a functional binding protein. The specifications (pg. 39) describe the CDRs 1-3 of Family 2, specifically defined by kabat numbering, whereby the CDR1 has 2 X residues (out of 5 total), the CDR2 has 1 X residue and the CDR3 has 3 X residues. This allows for a vast number of variant embodiments if the X residues are not defined. There is no evidence that all the possible variant CDRs 1-3 can be mixed and matched to result in a functional binding domain. This is repeated in new claim 35, which claims any functional orthologue of SEQ ID NOs: 1-5. Applicants cannot claim a genus of structures, based on function, whereby the artisan must do the work of determining which of the claimed hypothetical combinations will actually work. The claims should be drawn to the invention that was made. If variability is tolerated at specific residues, applicants should describe both the structural properties that are required and not variable, as well as the specific variability that is tolerated at specific variable residues. There should be descriptive support demonstrating how the applicants came to the conclusion regarding the structure/function relationship; such that the artisan is informed as to which hypothetical combination works. If applicants are relying on the idea that some CDR variants are almost identical, as the basis for concluding that swapping CDRs, or CDRs with variant residues, will result in a functional binding domain, the examiner is making clear that the position of the Office and the antibody art does not support that “almost identical” CDRs can be presumed to function appropriately. Instead the antibody art teaches that binding proteins require explicit sequence structure to generate a functional protein with specificity for a single target epitope, and that changing even a single amino acid residue in a CDR domain can significantly alter or even de-functionalize the protein. Thus, varying amino acid residues within a base structure requires generating the variants to define which alternative amino acids may be tolerated at any given residue location. This is made more difficult when claim 1 leaves open the interpretation of what residues even define the CDR. The applicants do not have descriptive support for the breadth of definitions and combinations as recited in claim 1. Applicant’s arguments support descriptive support for the 5 variant species of Family 1, with explicitly defined CDRs with corresponding SEQ ID NOs, in combination; such embodiments which may be searched and examined for novelty. However, claim 1, as written, still suffers from a lack of descriptive support to cover the breadth of the claim. Thus the rejections are maintained.
Conclusion
No claims are allowed. As the elected species of claim 1 is not allowed, no other species have been searched. As the invention of Group I is not allowed, the methods of Group II, claims 26-31, are not rejoined or examined.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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