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 .
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 Claims 26-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups III and IV, there being no allowable generic or linking claim.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. 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 Claims 17-21 are withdrawn as not reading on the elected species.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 or 53-55 comprise the CDRs 1-3 of SEQ ID NOs: 9, 14 and 15, respectively.
Status of Claims
Claims 1-11, 14-22, 25-34 are pending; claims 17-21 and 26-31 are withdrawn; claims 1-11, 14-16, 22, 25 and 32-34 are being examined on the merits.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1, line 14, recites “any of SEQ ID NOs: 1 to 5 or SEQ ID NO: 53-55”. The “NO” should be plural (i.e. “NOs:”) in both instances for consistency. Further, reference to ID NOs: 1 to 5 and 53-55 are using inconsistent nomenclature. They should each be 1-5 and 53-55, or 1 to 5 and 53 to 55. Appropriate correction is required.
Claims 1, 3-4, 6-8 and 14 are objected to because of the following informalities: In some instances the claims recite SEQ ID NO:30 with no space between the colon and the number, in other instances the claims recite SEQ ID NO: 1, with a space. There should be a space between the colon and the number, and it should be consistent across the claims when identifying any “SEQ ID NO:”. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: Claim 7, line 5, recites “at least oneof the amino acids”. This is a typo, there should be a space between “one of”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: Claim 16, line 14, recites “ID NO: 23 23,”. This is a typo, “23” is unnecessarily repeated. 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.
Claims 1-11, 22, 25 and 32-34 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 or SEQ ID NOs: 53-55, wherein the CDRs are annotated according to Kabat, MacCallum, IMGT, AbM, or Chothia.” As the binding agent is defined as an immunoglobulin single variable domain (ISVD), and it is known that the variable domains of an immunoglobulin comprise a set of 3 corresponding CDRs which impart the binding specificity to the ISVD, thus it is clear that the claimed ISVDs must have 3 corresponding CDRs. See the specifications which describe “the CDRs of the ISVD biding agents described herein can therefore be described as the CDR sequences as present in the single variable domain antibodies described herein,” (Specs., pg. 79, lines 2-4). What is unclear is what those CDRs are, and where they come from. In claim 1, the phrase “the CDRs present in any of SEQ ID NOs: 1-5”, whereby it is known that SEQ ID NOs: 1-5 represent full length VHH binding molecules with 3 CDRs (specs., pg. 37), suggests that the 3 CDRs are chosen from the same individual VHH. That is, all 3 CDRs are derived from either SEQ ID NO: 1, or SEQ ID NO: 2, or SEQ ID NO: 3, etc. However, the elected species of ISVD (see Remarks of 4/9/2026) comprises CDRs 1-3 of SEQ ID NOs: 9, 14 and 15, respectively; which are not, as a set, recited in any single VHH of SEQ ID NOs: 1-5. Claim 14, which depends from claim 1, recites CDRs as sequences comprising X residues, which seems to attempt to allow for differences in, for example CDR2 derived from any of SEQ ID NOs: 1-5. Claim 15, which depends from claim 14, recites mixing and matching CDRs derived from across the various VHHs of SEQ ID NOs: 1-5. Thus, it is unclear whether the CDRs of the ISVD of claim 1 are derived from a single VHH, which may be any one of those represented by SEQ ID NOs: 1-5 or 53-55, or are mixed and matched CDRs across any of the VHHs, or only require any single CDR sequence derived from any of the VHHs, whereby the remaining CDRs and FR domains may be derived from other sources. Thus, the scope of the CDRs for use in the ISVDs of claim 1 is unclear. Further, claim 1 does not define the residues that make up the CDRs that are required to meet the claim limitation. It is known in the art that binding proteins may have their CDRs defined differently, such as according to Kabat vs IMGT vs Chothia numbering schemes. However, if CDRs are being derived from any of SEQ ID NOs: 1-5 and 53-55, mixed and matched, and further comprising different framework regions, then it is necessary for the skilled artisan to have a clear definition of the amino acid residues that define the CDRs of the invention. Here it is unclear what regions of the cited sequences the applicant considers as a CDR for use in the invention. Therefore, 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 32-34 depend from claim 1, but fail to rectify the issue of indefiniteness, they are also rejected.
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, 14-16, 22, 25 and 32-34 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 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 24 CDRs of SEQ ID NOs: 1-5 and 53-55. Further, claim 1 recites whereby the CDRs of SEQ ID NOs: 1-5 and 53-55 are defined by any of the Kabat, MacCallum, IMGT, AbM, or Chothia numbering schemes. 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 53-55, and whereby the explicit amino acid sequences of the CDRs are alternately defined; thus claim 1 is drawn to a vast number of ISVD alternatives. Claim 14 further limits the CDRs 1-3 of the ISVD to SEQ ID NOs: 6-8, respectively, whereby each of SEQ ID NOs: 6-8 comprise X residues, which may be any of the 20 amino acids. The CDR1 of SEQ ID NO: 6 has 1 “X” residue, and therefore offers 20 alternate CDR1s (i.e. 201). The CDR2 of SEQ ID NO: 7 has 5 “X” resides and therefore offers 205 alternate CDR2s; the CDR3 of SEQ ID NO: 8 has 1 “X” residue and therefore offers 201 alternate CDR3s. Therefore, claim 14 encompasses a genus of ISVDs comprising at least 207 different CDR sequences, not including any manner of combining the 3 alternate CDRs into a corresponding set of CDRs in a single ISVD. Thus, claim 14 is drawn to a vast number of embodiments. Note that even if the X residues of claim 14 were limited to 2 alternative amino acids for each residue, the claim would still encompass 128 variant embodiments. Claim 15, which depends from claim 14, further limits the ISVD to those comprising CDRs 1-3, whereby CDR1 may be either of SEQ ID NO: 9 or 10, CDR2 may be 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.
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, 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 six 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, 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, 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 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. 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, for example, the CDR3 of SEQ ID NO: 53 with CDRs 1-2 of SEQ ID NO: 1 would result in 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 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, 14 and 15 are rejected for lack of adequate written description support. Claims 2-11, 16, 22, 25 and 32-34 are also rejected as they are dependent on rejected claim 1.
Allowable Subject Matter
It is noted that the elected species, an ISVD comprising CDRs 1-3 of SEQ ID NOs: 9, 14 and 15, respectively, has been searched and is free of the art. However, as no claims are presently deemed allowable, the search was not extended to further species.
Conclusion
No claims are allowed.
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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/JAMES RYLAND MELCHIOR/ Examiner, Art Unit 1644
/NELSON B MOSELEY II/ Primary Examiner, Art Unit 1642
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