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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of species: taxane, cisplatin, lung cancer, non-small cell lung cancer, docetaxel, cisplatin, SEQ ID NOs: 84-89 and 92-95, 7-B16 antibody, pembrolizumab in the reply filed 07/31/2026 is acknowledged.
Claims 8, 11, and 33 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 07/31/2026
Claims 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64 are now under consideration in the instant Office Action.
Claim Objections
Claims 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64 are objected to because of the following informalities: the instant claim does not explain the acronym “CCR8” at its first iteration. The acronym must be fully spelled out prior to its first iteration, after which point it may be used in place of the term it acronymizes. 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 and 62 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.
Instant claim 1 recites the term “optionally”. The phrase “optionally” is interpreted as "for example" which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. For the purposes of examination, the instant claims will be interpreted without the optional limitations as they are not required or claimed as necessary to the invention.
Instant claim 62 recites a “7-B16 antibody”. There is no structure or sequence(s) recited in the disclosure or sequence listing for the antibody. As such, it is unclear what the identity of the antibody is or if it is related to the CDR sequences listed in a preceding claim.
Instant claim 62 also recites several antibodies by their laboratory name distinctions and lists an additional name in parentheticals following it. It is unclear if the name in the parentheticals are the name of the company that produced the antibody, additional nomenclature for the antibody, or another way of identifying the antibody. Applicant is reminded that parentheticals in claims are used to abbreviate a previous listed term.
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 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64 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.
Claims 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64 are directed to any antibody that binds CCR8, wherein the anti-CCR8 antibody has antibody-dependent cellular cytotoxicity activity and/or complement-dependent cytotoxicity activity. As such, the claim is directed to an antibody defined entirely by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence (for CCR8) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (in instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, 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 (p.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 page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen et al., 1995 (in instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
The instant specification discloses groups of six heavy chain and light chain CDR sequences that make up an antibody on pages 34-44, as well as the heavy and light chain variable region sequences which comprise them. However, as discussed above, without any way to determine how broad the genus of such antibodies are, there is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies. Additionally, Applicant recites a “7-B16” antibody in instant claim 62 which does not have a structure listed in the sequence listing or in the instant specification. In order to show possession, Applicant must provide a structure for the antibody.
Instant claims 49 and 55 recite heavy and light chain variable region sequences with at least 90% identity to SEQ ID NOs: 68-69, 74-75, 92-93, and 96-97. In addition to claims 49 and 55 depending from a claim without recitations of sequences, there is no limitation or exclusion in the claim language that prevents the modifications from occurring within the CDR region due to the claim language allowing up to at least 90% sequence identity, which widens the scope of the claim to encompass an immense number of unknown molecules that share 90% identity to the claimed sequence and can bind to the claimed receptor. Applicant has not demonstrated that they are in possession of all the molecules that fall within the immense scope of the claim that are able to achieve the claimed function.
Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs. Moreover, CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies. For example, WO 2008068048 (in instant PTO-892) discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 (in instant PTO-892) describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. The instant claims fail to specify what specific sequences constitute the six CDRs of the antibody capable of binding to the target antigen.
As such, the disclosure of a large list of CDRs does not convey possession of all the potential antibodies that would arise from the claims as recited and have the same binding properties; possession of the precisely defined sequences of the six CDRs is required. As such, the specification fails to set forth a structure-function correlation sufficient to claim all possible antibodies defined by function and one-three CDRs or alterations thereof.
With respect to product claims 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64, it is recognized that information which is well known in the art need not be described in detail in the specification (MPEP §2163(II)(A)(2)). See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention is in a new antibody, or at the least disclosure of a new antibody that could not have been envisaged from the prior art indicates that the prior art was not in possession of all “anti-CCR8” antibodies. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed, does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as antibody that binds to CCR8, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of anti-CCR8 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (in instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of antibodies that binds to CCR8. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
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. 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.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed antibodies with specific CDR sequences and heavy and light chain variable sequence pairs, the skilled artisan cannot envision the detailed chemical structure of all of the potential encompassed combination of antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64 do not meet the written description requirement.
Claims 1-2, 6, 9-10, 24, 29-30, 32, 34, 38, 48-49, 55, 57, 62, and 64 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-CCR8 antibody with the claimed CDR sequences, does not reasonably provide enablement for any anti-CCR8 antibodies that are claimed functionally without fully defined sequences. 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.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include but are not limited to:
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The breadth of the claims;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The nature of the invention;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The state of the prior art;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The level of one of ordinary skill;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The level of predictability in the art;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The amount of direction provided by the inventor;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The existence of working examples; and
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to this rejection are 1) the breadth of the claims, 2) the state of the prior art, and 3) the amount of direction provided by the inventor. In the instant case, the amount of direction provided by the inventor, the breadth of the claims, and the state of the prior art disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue experimentation.
The Breadth of the Claims
The claims as currently written are extremely broad. The instant claims drawn to any anti-CCR8 antibody, a chemotherapeutic agent, and an anti-PD-1 antibody, wherein the anti-CCR8 antibody has antibody-dependent cellular cytotoxicity activity and/or complement-dependent cytotoxicity activity. The anti-CCR8 antibody is claimed functionally, as some of the instant claims do not recite any structure at all, while others recite very little structure that is subject to variability. The instant claims recite that the anti-CCR8 antibody further comprises heavy and light chain variable domains comprising an amino acid sequence of the recited SEQ ID NOs or an amino acid sequence having at least 90% identity to the recited SEQ ID NOs. However, these claims which encompass variability depends from claim 1, which only recites the antibody functionally and does not provide a structure that is subject to change. As such, the claims are drawn functionally and broadly.
The State of the Prior Art/Level of Unpredictability in the Art
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally 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 et al., in instant PTO-892). 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 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).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments and mutated antibodies of the instant claims as broadly as claimed.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
The Amount of Direction Provided by the Inventor/Existence of Working Examples
The instant specification provides exemplary antibodies, defined by their full heavy chain and light chain CDR sequences and heavy and light chain variable sequences. It is specifically noted that these exemplary antibodies comprise the full-length sequences of CDRs recited in instant claim 48; there are no exemplary antibodies provided that comprise fragments of the recited sequences nor mutations of the recited heavy and light chain CDR sequences. Based on the language of the instantly rejected claims which allows for up to 10% of the amino acid sequences to be modified, the specification does not provide sufficient disclosure for all of the potential combinations that can arise from this scale of modifications that are encompassed within the claim language.
In view of the of the breadth of the claims, the level of predictability in the art to which the invention pertains, as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies and antigen-binding fragments thereof comprising fewer than the complete VH/VL sequences for the antibody with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively make and practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
Prosecution Insights