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
1. Applicant’s election without traverse of Group I, encompassing claims 1-2, 4-6, 9, 14, 16-19, 22-23, 29, 28-29 and 31-33, in the reply filed on May 12, 2026 is acknowledged. New claims 44-46 are also directed to the invention of Group I.
2. Claims 1, 16 and 18 have been amended and claims 12, 37 and 40-42 (Groups II-V) have been canceled in the amendment filed May 12, 2026. Accordingly, claims 1-2, 4-6, 9, 14, 16-19, 22-23, 29, 28-29, 31-33 and 44-46 are pending and under examination in the current office action.
Information Disclosure Statement
3. The information disclosure statements (IDSs) filed 11/05/2024 and 08/07/2025 have been considered and the references therein are of record.
Claim Objections
4. Claims 23 and 33 are objected to because of the following informalities:
Claims 23 and 33 each recite the term “A-beta”, which is an abbreviation for amyloid-beta. This abbreviation should be spelled out in its first usage in the claims.
Claim 33 recites steps “a.” and “b.”, which steps contain periods after each of the letters “a” and “b”. MPEP 608.01(m) states that each claim begins with a capital letter and ends with a period, and periods may not be used elsewhere in the claims except for abbreviations. Therefore, it is suggested that claim 33 be amended to recite “(a)” and “(b)”, or else “a)” and “b)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
5. Claims 1-2, 4-6, 9, 14, 16-19, 22-23, 29, 28-29, 31-33 and 44-46 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:
An antibody that preferentially binds a cyclo(CGHHQKG) (SEQ ID NO: 2) peptide over a linear CGHHQKG (SEQ ID NO: 2) peptide, the antibody comprising:
a light chain variable region comprising the complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 having the sequences of SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively, and a heavy chain variable region comprising the complementarity determining regions CDR-H1, CDR-H2 having the sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and the CDR-H3 having a sequence selected from any one of SEQ ID NOs: 31-36, 38-40 or 42-50; or
a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 4 and a heavy chain variable region (VH) comprising an amino acid sequence selected from any one of SEQ ID NOs: 11-16, 18-20 or 22-30,
does not reasonably provide enablement for an antibody having less than the full set of six fully defined CDRs from the VH and VL domains (3 from each). 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 factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and, (8) the breadth of the claims. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
Claim 1 and dependent claims thereof are drawn to an antibody that preferentially binds to a cyclo(CGHHQKG) peptide over a linear (CGHHQKG) peptide, the antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), the VH comprising CDR-H1, CDR-H2 and CDR-H3, the CDR-H3 having a sequence selected from any one of SEQ ID NO: 31-36, 38-40 or 42-50. Preferential binding to this cyclic peptide epitope also conveys binding specificity to amyloid-beta (A-beta or Ab) oligomers, which are found to be present in biological samples from subjects having an amyloidogenic disease such as Alzheimer’s disease. Dependent claim 2 recites that the VL of the antibody comprises the CDR-L1 of SEQ ID NO: 8, the CDR-L2 of SEQ ID NO: 9 and the CDR-L3 of SEQ ID NO: 10. And dependent claim 4 recites that the VH comprises the CDR-H1 of SEQ ID NO: 5 and the CDR-H2 of SEQ ID NO: 6. The claims also are directed to a vector or nucleic acid molecule encoding the antibody of claim 1, and a method for determining if a biological sample contains an Ab oligomer, comprising contacting the sample with the antibody of claim 1. Hence, the claims encompass antibodies in which less than the full repertoire of six CDRs that comprise the antigen binding site of a typical antibody are defined.
In the present case, the nature of the invention is complex. In contrast to the broad scope of the claims, what is provided in the specification is quite narrow. The specification discloses only antibodies that contain both a VH and a VL chain with no less than six CDRs, three from the VH chain and three from the VL chain that bind to antigen, such as a parental monoclonal antibody and about 20 affinity-matured clones derived therefrom. However, in each of these instances a full set of three CDRs each for the light and heavy chain variable regions (or 6 CDRs total) are necessary for binding to the cyclic peptide (CGHHQKG). The specification does not enable antibodies or antigen-binding fragments thereof, which do not contain the full set of six CDRs corresponding to each clone.
It is well established in the art that the formation of an intact antigen-binding site of all antibodies requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, Third Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). 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, which 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 (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
For example, Padlan et al. (Proc Natl Acad Sci USA, 1989; 86:5938-5942) describe the crystal structure of an antibody-lysozyme complex where all six CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen (see entire document, but especially page 5940, right column, section under "Structure of the Combining Site"). It is also well established in the art that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA, 1982; 79(6):1979-1983). The Rudikoff et al. reference teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Thus, the state of the art recognizes that it would be highly unpredictable that an antibody comprising less than all six CDRs from an antibody with a desired specificity, or else an antibody having alterations in the variable regions, would bind the same antigen and/or bind with the required affinity. Hence, it is unlikely that the binding moieties as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function.
The specification does not provide guidance or working examples directed to antibodies having less than the full repertoire of six CDRs. Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict the ability of producing an antibody containing fewer than six CDRs that results in an antibody that retains the antigen specificity and affinity currently claimed (such as in claim 14 which recites that the antibody has a KD of at least about 2.5 x 10-11 for cyclo(CGHHQKG) peptide). One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly claimed. Therefore, in view of the lack of guidance in the specification and in view of the discussion above, undue experimentation would indeed be required to make and use the invention commensurate with the scope of the claims.
Reasonable correlation must exist between the scope of the claims and the scope of the enablement set forth. In view of the lack of guidance in the specification, the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the predictability of the art and the breadth of the claims, undue experimentation would be required to make and use the invention commensurate with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir., 1988).
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.
6. Claims 17, 26, 28, 32 and 33 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 17 recites that the antibody is an antibody binding fragment selected from “…scFv…or wherein the antibody is a single chain antibody”. However, this recitation renders the claim indefinite because an scFv is the abbreviation for a single chain antibody. That is, they are the same thing. Therefore, it is unclear whether two different types of antigen-binding fragment were meant to be recited or if the term has simply been repeated.
Regarding claim 26, the phrase "such as" (i.e., “such as PET imaging”) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 28 recites the limitation "the immunoconjugate" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 32 recites the limitations "the immunoconjugate" in line 1, “the nucleic acid molecule” in line 2, and “the vector” in line 2. There is insufficient antecedent basis for these limitations in the claim.
Claim 33 recites the limitation "the biological sample" in line 1. There is insufficient antecedent basis for this limitation in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
7. Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 17, which depends from claim 1, recites that the antibody may be a nanobody. Claim 1 recites that antibody comprises a VH and a VL. However, a nanobody, which is also known as a single-domain antibody or sdAb, is an antibody fragment consisting of a single monomeric VH domain, and therefore would not comprise a VL domain as required by independent claim 1. Claim 17 is thus improperly dependent because a nanobody (or sdAb) excludes a VL domain.
Applicant should note the “Infringement Test” for dependent claims in MPEP 608.01(n). The test for a proper dependent claim is whether the dependent claim includes every limitation of the parent claim. A proper dependent claim shall not conceivably be infringed by anything which would not also infringe the basic claim. In the instant case, the nanobody of claim 17 could be infringed without infringing the claim from which it depends, i.e., the antibody of claim 1. Therefore, the claim is improperly dependent.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
8. No claims are allowed.
The prior art does not teach or reasonably suggest an antibody comprising the CDR-H3 amino acid sequences of instant SEQ ID NOs: 31-36, 38-40 or 42-50, nor the VH amino acid sequences of SEQ ID NOs: 11-16, 18-20 or 22-30.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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