DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-3, 5-8, 11, 13, 18, 24, 29, 41, 46-50 and 53-55 are pending.
Claims 4, 9, 10, 12, 14-17, 19-23, 25-28, 30-40, 42-45, 51, 52 and 56-62 have been cancelled.
Claims 3 and 8 have been amended.
Claims 1-3, 5-8, 11, 13, 18, 24, 29, 41, 46-50 and 53-55 are examined on the merits.
Claim Objections
3. Claim 24 is objected to because of the following informalities: it depends from a cancelled claim, claim 22. Appropriate correction is required.
4. 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 1-3, 5-8, 11, 13, 18, 24, 29, 41, 46-50 and 53-55 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.
MPEP § 2163 states that 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, 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus take into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen.
The instant claims are drawn to an anti-CD147 antibody comprising alterations within the complementarity determining regions (CDRs) and methods of administering the said antibody. The claims recite an anti-CD147 antibody comprising at least 70% identity to specific CDRs comprising SEQ ID NOs: 16-39, as well as an anti-CD147 antibody comprising up to 5 amino acid modifications in at least one CDR and an antibody (claims 41 and 46) with only one defined variable region (claim 5). The claims read on a number of possible alterations within the CDRs regions that could affect antigen binding.
It is well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs that provide the majority of the contact residues for the binding of the antibody to its target epitope, see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1 within Almagro et al. (Frontiers in Bioscience 13: 1619-1633, January 1, 2008). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences, see Section 4 of Almagro. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody, see Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening, see Almagro, Sections 4 and 5.
Examples of antigen binding domains comprising only a VH (or less commonly, a VL) that in turn comprise only three CDRs certainly do exist in the literature, but those antibodies generally comprise unique structures such as CDR1 and CDR3’s that are elongated in length and that are often disulfide linked (see De Genst et al., Developmental and Comparative Immunology 30:187-198, available online 11 July 2006. “Shuffling” of the VL (or less commonly the VH) had also been used to improve affinity of a parent antibody in certain instances. But the procedure generally required a "dominant" VH (i.e., a VH that is primarily responsible for antigen specificity), see Yoshinaga et al., (J. Biochem 143:593-601, published online January 23, 2008).
Applicant’s specification discloses VhH antibodies with defined pairings of CDRs 1-3 (see table 2 on pages 18-19), however instant claim 1 is drawn to an “anti-CD147 antibody” which reads on a full-length antibody having a VL and VH and does not limit the claims to a single domain antibody. Instant claim 5 is drawn to a full length anti-CD147, however only defines the sequence of the variable heavy chain.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the [7,070,775] patent possessed such an antibody.”) Absent the conserved structure provided by CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
MPEP § 2163 states that 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.
The specification does not provide guidance on which 30% of amino acid residues within the CDRs can be altered and still retain antigen binding to CD147, however the claims as written encompass a broad scope of a large number of possible mutations. As noted above, the art generally accepted that the combination of the CDRs were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antibodies other than those comprising 100% to the CDRs instantly claimed.
Although Applicants may argue that it is possible to screen for antibodies which can bind to serum albumin, however the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.”
In view of the prior art teaching, mentioned above, that variations within the CDRs render antigen binding unpredictable, one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of variant single domain variable antibodies recited in the instant claims. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera. Applicant is invited to amend the claims to recite 100% identity to CDR1, CDR2, and CDR3 or VH and define any modifications by residue and amino acid substitution as well as amend the claims to the intended invention of a single domain VhH antibody as disclosed in the specification.
6. 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 6, 18 and 50 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 6 contains the trademark/trade name NANOBODY® on line 5 of the claim. 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 single-domain antibody fragments, accordingly, the identification/description is indefinite.
On lines 5 and 6 of claims 18 and 50, cite “…immunodeficiency virus (e.g. HIV)”. The acronym, e.g. is an abbreviation meaning “for example”. This is exemplary language, which is indefinite because the scope of the claim is not clear, as well as it is not clear if the language following the term is an example or preference. Hence, the metes and bounds cannot be determined.
Conclusion
8. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
January 6, 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643