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 .
Election Restrictions
Applicant’s election without traverse of Group I, claims 1, 4, 12, 13, 16, 19, 27, 29-32, 44, 46, 47, 51, 54, 59, 61, 64, 65-68 drawn to an isolated antibody or antigen-binding fragment thereof, in the reply filed on 10/28/2025 is acknowledged. Additionally, Applicant’s election of the following species”
A set of CDR amino acid sequences: SEQ ID NOs: 74, 75, 76, 78, 79, and 80 (R217) [CL3.1] in claim 1
A set of CDR amino acid sequences: SEQ ID NOs: 74, 75, 76, 78, 79, and 80 (R217) [CL3.1] in claim 4
SEQ ID NOs: 74, 75, 76, 78, 79, and 80 for VH-CDR1,
VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, respectively, in claim 12
VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, respectively, in claim 13
SEQ ID NO: 73 and SEQ ID NO: 77 (R217) [CL3.1] as a VH and a VL, respectively, in claim 16
SEQ ID NO: 73 and SEQ ID NO: 77 (R217) [CL3.1] as a VH and a VL, respectively, in claim 19
in the reply filed on 10/28/2025 is acknowledged.
Claims 52, 69, 71, 72, 74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 1, 4, 12, 13, 16, 19, 27, 29-32, 44, 46, 47, 51, 54, 59, 61, 64, 65-68 are under examination on the merits.
Priority
Applicant’s claim for domestic benefit of prior-filed provisional application No. 63/053,987 filed on 07/20/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 09/13/2023 and 10/16/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings were received on 01/19/2023. The drawings are objected to because the labels should read “FIG.” instead of “FIGURE”. Further, the graphs in Figure 4A are difficult to read because the resolution is too low.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, for example in page 15. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term “FACS Aria III” on page 49, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that “FACS Aria III” is merely an example and all improper uses of trademarks in the specification should be identified by Applicant and properly addressed.
Claim Objections
Claims 16, 19, 27, 44 and 51 are objected to because of the following informalities:
On claims 16 and 19, the recitation of “identical to reference amino acid sequences” should read “identical to amino acid sequences”. Appropriate correction is required.
On claim 27, the recitation of “NHP antibody” should be defined at first mention. Appropriate correction is required.
On claims 44 and 51, the recitation of “a filovirus virus” should read “a filovirus” or “a filovirus particle”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 12, 13, 16, 19, 27, 29-32, 44, 46, 47, 51, 54, 59, 61, 64, 65-68 are rejected on the basis that they contain, explicitly or inherently, 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). 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 of processes, 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 described alternative chemical compounds whether by words or chemical formulas and 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 form the substantial structural feature. See MPEP 706.03(y).
The Markush grouping of antibody CDRs or variable sequences are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Each of the variable heavy or light chain sequences listed in the instant claims comprise structurally distinct sequences and sets of CDRs sequences that do not all share a "single structural similarity". Each of the sets of CDRs listed in the instant claims comprise structural distinct sequences that do not all share a "single structural similarity" or share a substantial structural feature.
The instant claims list sets of sequences corresponding to CDRs or variable regions of large number different antibodies disclosed in the Specification. Not all of the sets of CDRs in instant claims share a "single structural similarity". The Specification as well as instant claims note distinct clonal lineages to which the antibodies belong (pages 3, 23). The clonal lineages indicate how the different sets of CDRs are related to one another. For example, the VL-CDR3 amino acid sequences of the Clonal Lineage 6 antibodies share a consensus sequence (Specification, page 23) which is considered a shared "single structural similarity". Based on these single shared structural similarities among members of each clonal lineage, it is herein submitted that each lineage represents a proper grouping of alternatives. Further, based on Applicant’s election of a set of CDR amino acid sequences comprising: SEQ ID NOs: 74, 75, 76, 78, 79, and 80 (R217) belonging to clonal lineage 3, it is here noted that the Markush grouping considered for a rejoinder in instant application will consist only of those sets of CDR amino acid sequences of antibodies belonging to clonal lineage 3.
Claim Rejections - 35 USC § 112 - Written Description
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 1, 4, 12, 13, 16, 19, 27, 29-32, 44, 46, 47, 51, 54, 59, 61, 64, 65-68 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 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 inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he 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.' (internal quotation marks omitted).").
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
The instant claims require an isolated antibody or antigen-binding fragment thereof comprising VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL- CDR3 amino acid sequences identical to SEQ ID NOs: 74, 75, 76, 78, 79, and 80, respectively. It is noted that claims 12 and 13 are directed to an isolated antibody or antigen-binding fragment thereof comprising sets of CDRs (VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL- CDR3) wherein the sets of CDRs are comprised by composite groups made up of different combinations of CDRs as listed in the claims. For example, an antibody or antigen-binding fragment thereof according to claims 12 and 13 could have a VH-CDR1 comprising SEQ ID NO: 74 (which is part of Applicant’s elected species) which corresponds to the antibody R217; and a VH-CDR2 comprising SEQ ID NO: 83, which corresponds to the antibody R224 (which is not Applicant’s elected species). The instant claims alternatively require an isolated antibody or antigen-binding fragment thereof comprising VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL- CDR3 amino acid sequences identical except for four, three, two, or one single amino acid substitutions, deletions, or insertions in one or more CDRs to SEQ ID NOs: 74, 75, 76, 78, 79, and 80. The instant claims alternatively require an isolated antibody or antigen-binding fragment thereof comprising a VH and VL amino acid sequences at least 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to amino acid sequences SEQ ID NOs: 73 and 77, respectively. It is noted that SEQ ID NOs: 73 contains SEQ ID NOs: 74, 75, 76; and SEQ ID NOs: 77 contains SEQ ID NOs: 78, 79, 80. As such the instant claims comprise an isolated antibody or antigen-binding fragment thereof wherein sequence alterations can be made anywhere in the CDRs or anywhere in the amino acid sequences encoding the VH and VL, provided that one or more of the CDRs has at most 4 single amino acid alterations; or provided that the VH and VL amino acid sequences bears at least 85% sequence homology to SEQ ID NO: 73 and 77, respectively, wherein the 15% lack of identity is undefined and encompasses sequences with deletion(s), insertion(s) and/or substitution(s) at any position(s) in the VH and VL sequences indicated.
With respect to the amino acid sequences encoding the VH and VL regions, namely SEQ ID NO: 73 and 77, it is noted that they are 119 and 110 amino acids long, respectively. The instant claims encompass anywhere from 1 to 17 and 1 to 16 respectively, substitutions, deletions, or additions in any combination along any length of SEQ ID NO: 73 and SEQ ID NO: 77. Thus, an enormous genus (2017 = 1.3 x 1022 ; 2016 = 6.55 x 1020) comprising trillions upon trillions of sequences is encompassed by the tremendously broad scope of the claims. Functionally, however, the instant claims require that such genus of variants exhibit binding to a conserved Marburg virus or Ravn virus epitope.
However, while the claims are drawn to a genus that comprises innumerable sequences, the Specification fails to provide an adequate number of species that would represent the claimed genus of variants possessing the functional properties as required by the claims. For example, the sequence set forth in SEQ ID NO: 73 is a VH region, however the Specification fails to provide which residues could tolerate a substitution yet still maintain the binding affinities as claimed. Further, with respect to claims 12 and 13, the Specification fails to provide which combinations of CDRs can be grouped together into a single antibody or antigen-binding fragment thereof and yet still maintain the binding affinities as claimed.
At best, the Specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Thus, one of skill in the art would readily appreciate that relying on a non-patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
It is known in the art that even the most minor differences can have significant effects on antigen-antibody binding ability; see Rudikoff et al. ("Single amino acid substitution altering antigen-binding specificity," Proc Natl Acad Sci USA 79:1979-1983 (1982)(See 892-Notice of References Cited). The art relating to antibodies recognizes that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity that is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. 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. Further, as Rudikoff et al. teach, alterations of a single amino acid in the CDR regions of a phosphocholine-binding myeloma antibody or antigen-binding fragment thereof resulted in the loss of antigen-binding function.
Further, Goel et al. (“Plasticity within the Antigen-Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response,” J. Immunol. 173: 7358-7367 (2004))(See PTO-892: Notice of References Cited) teaches antibodies that bind to the same 12-mer but have very different CDRs; Lloyd et al. (“Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens,” Protein Engineering, Design & Selection, Vol. 22, No. 3: 159-168 (2009))(See PTO-892: Notice of References Cited) teaches: on average, about 120 different antibodies in a library can bind to a given antigen; Edwards et al. (“The Remarkable Flexibility of The Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLys,” J. Mol. Biol. 334: 103-118 (2003))(See PTO-892: Notice of References Cited) teaches: a library contained over 1000 antibodies that bound to a single 51kDA protein, including unique VH and 705 VL sequences; there were 568 different CDR3 regions. Given the highly diverse nature of antibodies, particularly in the CDRs, one of ordinary skill in the art generally cannot envision the structure of an antibody by knowing its binding characteristics (for example as instantly claimed, specific binding to a conserved Marburg virus or Ravn virus epitope).
Therefore, in light of the knowledge in the art, the broad scope of the claims, and the teachings in the Specification, it is asserted that there is still a high level of uncertainty as to which antibodies fall within the scope of the indicated genus while retaining the ability to bind a conserved Marburg virus or Ravn virus epitope.
In the absence of a representative number of examples, the Specification must at least describe the structural features that are required for the claimed function, in this case binding to a conserved Marburg virus or Ravn virus epitope. However, as discussed above, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to binding to a conserved Marburg virus or Ravn virus epitope.
Thus, in view of the reasons set forth above, the claims as currently written are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus at the time of filing.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-F 8-5.
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/MARLENE V BUCKMASTER/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672