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, 3, 8-9, 11, 14, 16-19, 21, 25 and 28, in the reply filed on July 5, 2026 is acknowledged.
2. Claims 31-37, 39, 43 and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 5, 2026.
3. Claims 1, 3, 8-9, 11, 14, 16-19, 21, 25 and 28 are under examination in the current office action.
Information Disclosure Statement
4. The information disclosure statements (IDSs) filed 10/13/2023, 10/15/2025 and 03/31/2026 have been considered and the references therein are of record.
Specification
5. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
It is suggested that Applicant omits the word “NOVEL” from the title. Novelty is a legal concept and does not describe the invention claimed. Novelty is required of all claimed inventions before they are issued as patents. To use the term in the title would imply merit in the regard without actual examination. Although MPEP § 606.01 does not specifically refer to use of the term “novel”, it is similar to the term “improve” which also implies merit without examination.
Claim Objections
6. Claims 1, 3 and 11 are objected to because of the following informalities:
Claim 1 recites an acronym that is not spelled out in its first use in the claims (i.e., hVEGFR). It would be remedial to amend the claim language in claim 1 such that the acronym is clearly defined. Appropriate correction is required.
In choice (a) of claim 3, “a HCDR2” should be amended to recite “the HCDR2”. Appropriate correction is required.
Similarly, claim 11 is directed to an antibody or antigen-binding fragment thereof wherein “a) the heavy chain variable region comprises a sequence of SEQ ID NO: 58 and the light chain variable region comprises a sequence of SEQ ID NO: 59” (emphasis added). Selections (b), (c) and (d) recite similar claim language. However, the broadest reasonable interpretation (BRI) of comprising “a sequence of SEQ ID NO: XX” reads upon a variable region sequence that comprises within it a short peptide fragment of the specifically recited sequences. In other words, the entirety of sequence of SEQ ID NO: 58 (or 59 or 60, etc.) is not required to meet the BRI of the claim. Therefore, it is suggested that selections (a)-(d) be amended to recite “the sequence of SEQ ID NO:…” in each instance within the claim. 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.
7. Claims 16, 18 and 21 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 16 is indefinite because it depends from canceled claim 15. The metes and bounds of the claim therefore cannot be readily determined because it depends from canceled subject matter.
Claim 18 contains the trademark/trade name nanobodyTM. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a VHH antibody or single domain antibody and, accordingly, the identification/description is indefinite.
Regarding claim 21, the phrase “(e.g., VEGFR3)” (that is, "for example, VEGFR3") renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
8. Claims 1, 3, 8-9, 11, 14, 16-19, 21, 25 and 28 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 anti-human vascular endothelial growth factor receptor (hVEGFR) antibody or antigen-binding fragment thereof, comprising heavy chain HCDR1, HCDR2 and HCDR3 and light chain LCDR1, LCDR2 and LCDR3 sequences, wherein:
the HCDR1 sequence comprises SEQ ID NO: 41, the HCDR2 sequence comprises SEQ ID NO: 42, the HCDR3 sequence comprises SEQ ID NO: 43, the LCDR1 sequence comprises SEQ ID NO: 28, the LCDR2 sequence comprises SEQ ID NO: 29, and the LCDR3 sequence comprises SEQ ID NO: 30 (with X1, X2, X3 and X19 residues as defined in claim 1),
does not reasonably provide enablement for an antibody having less than the full set of six defined CDRs from the VH and VL domains (three from each variable region). 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).
The instant claims are broadly drawn to a genus of antibodies or antibody fragments against human vascular endothelial growth factor receptor 2 (hVEGFR2), wherein the antibodies or antigen-binding fragments comprise heavy chain HCDR1, HCDR2 and HCDR3 and/or light chain LCDR1, LCDR2 and LCDR3. Thus, the claims encompass a genus of antibodies or antigen-binding fragments defined by a partial structure, either three HCDRs or three LCDRs. Dependent claims 3, 9 and 11 merely define the specific sequences comprised by the HCDRs, LCDRs, VH and VL regions. However, the broadest reasonable interpretation (BRI) of these claims still encompasses an antibody or antigen-binding fragment in which only three CDRs (3 HCDRs or 3 LCDRS) are required and defined, even when those CDRs are comprised by a VH or VL sequence.
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 the VEGFR2-specific hybridoma monoclonal antibodies designated Ab042, Ab048 and Ab054, and humanized versions thereof. 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 VEGFR. 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 currently claimed. Furthermore, no examples or guidance is provided for antibody fragments such as a domain antibody, a bivalent domain antibody, a Fd, a camelized single domain antibody, or a nanobodyTM, that comprise only a VH or a VL of said antibodies that bind to hVEGFR. 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).
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.
9. Claim 18 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 18 is drawn to an antibody or antigen-binding fragment thereof of claim 1. One embodiment of claim 1 is that of an anti-hVEGFR antibody or antigen-binding fragment comprising heavy chain HCDRs 1-3 and light chain LCDRs 1-3. Claim 18 recites that the antibody is a Fd, a camelized single domain antibody, a nanobody, a domain antibody, or a bivalent domain antibody. These antibody or antigen-binding fragment species, however, are outside the scope of antibodies of claim 1 comprising six CDRs because these species of claim 18 each comprise less than six CDRs.
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 antibody or antigen-binding fragment of claim 18 that is a Fd, a camelized single domain antibody, a nanobody, a domain antibody, or a bivalent domain antibody could be infringed without infringing the claim from which it depends, i.e., the antibody or antigen-binding fragment claim 1. Therefore, the claims are 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
10. No claims are allowed.
11. The prior art does not teach or otherwise suggest an anti-hVEGFR antibody or antigen-binding fragment thereof that comprises the recited VH and VL CDR sequences, or that comprises a pair of the claimed VH and VL sequences.
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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