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 .
Claim Status
Applicant’s amendment filed May 2, 2023 has been received and entered.
Claims 1-30 have been canceled.
Claims 31-59 have been added.
Claims 31-59 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/EP2021/080564 filed November 3, 2021, which claims the benefit of foreign application EP 20205442.5 filed November 3, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing” as a separate part of the disclosure or a CRF of the “Sequence Listing” for one or more amino acid sequences.
Claim 49 (line 4) there is no Sequence Listing for the following amino acid sequence:
Peptide Linker = (GGGGS)n
Required response - Applicant must provide:
An updated "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency – Amino acid sequences appearing in the claims and the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequences with 4 or more amino acids require a sequence identifier.
Claim 49 (line 4) and Specification (pg. 7, 46) recite the peptide linker (GGGGS)n, however, the amino acid sequence does not have a sequence identifier (SEQ ID NO).
All amino acid sequences more than 4 amino acids in length must be identified by their sequence identifier (i.e., SEQ ID NO).
As stated above, the amino acid sequence (GGGGS) does not appear in the Sequence Listing and does not have a sequence identifier. The sequence identifier must be added to the claim and specification upon submission of a new Sequence Listing.
Required response – Applicant must provide:
Amended claims in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 34, 40, 45-46, 50, 55-57, and 58 are objected to because of the following informalities:
Claim 34 (line 2) - should read “or a protein or other molecule…”.
Claim 40 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim appears to be a dependent claim, reciting “the method of any one of claim 31”. See MPEP § 608.01(n). Accordingly, the claim has not been further treated on the merits.
Claim 45 - should read “…wherein the immune cell is a cell expressing CD28, CD3, and a T cell receptor (TCR)”.
Claim 46 recites “CD3/TCR signaling is activated by treatment, or endogenously in response to a disease-associated antigen”. Although the claim is not indefinite, the language is confusing. It is suggested the claim be amended to read “…CD3/TCR signaling is activated by treatment or in response to a disease-associated antigen”.
Claim 50 (iv) recites the term “second signals”, which is defined in the instant disclosure as “additional costimulatory signals” [1]. As such, it is suggested that the claim be amended to recite “(iv) reagents that block additional suppressive costimulatory signals , via checkpoint molecules such as PD 1.”
Claims 55-57 - should read “the isolated binding molecule of claim 54”.
Claim 58 (lines 1-2) recites “The pharmaceutical composition of claim 57, further comprising an isolated further binding molecule”, which is grammatically awkward. It is suggested that the claim be amended to read “The pharmaceutical composition of claim 57, further comprising an additional isolated binding molecule:”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 33, 37, 42-43, 49-53, and 58-59 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 33, 50, 52-53, and 58 recite the term “such as”, which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 51 is included in the rejection because it depends from a rejected claim and fails to clarify the issue.
Claim 35 recites antigenic target proteins endoglin, FAB, and B7H2. It is unclear what a FAB protein is. The term appears once in the disclosure in an incomplete sentence that reads “fibroblast activation protein (FAB”, so it is unclear whether the protein should read FAP. If this is the case, the full protein name should be written out accompanied by its acronym.
Claim 37 recites the term “alternatively”, which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h).
Claim 42 recites “the at least two first antigen binding sites comprise an antibody heavy chain sequence and an antibody light chain sequence, each derived from, and competitively binding to the same antigen as, the C-terminal binding site comprised in an antibody sequence shown in SEQ ID NO: 2, 3, 4, 5, 7, 8 or 9.”; and
Claim 43 recites “the at least one second antigen binding site comprises an antibody heavy chain sequence and an antibody light chain sequence, each derived from, and competitively binding to the same antigen as, the N-terminal binding site comprised in an antibody composed of SEQ ID NO: 1 and 2”.
It is unclear what the relationship is between the C-terminal binding site and N-terminal binding site and the recited SEQ ID NOs. Specifically, the instant specification does not define what amino acid residues comprise the C-terminal binding site or N-terminal binding site for each recited SEQ ID NO, and it is unclear whether the binding site comprises the entire recited amino acid SEQ ID NO sequence, or some portion of the sequence. Further, the claim is dependent from claim 31 which recites that the antigen binding sites are antigen binding fragments of an antibody, however, it is unclear whether the amino acid sequences are fragments of an antibody, or if the fragments are (undisclosed) portions of the claimed sequences. Therefore the structure (i.e., amino acid sequence) of the first and second antigen binding sites cannot be clearly understood.
Claims 49 and 53 recite the limitations “preferably” and “further preferably”. The use of the phrase “preferably” render the claims indefinite because one cannot ascertain the metes and bounds of what is and what is not allowed. The examiner contends that the use of such preferences may lead to confusion over the intended scope of the claim. See MPEP § 2173.05(d).
Claim 53 recites the limitation “in particular”. The use of the phrase “preferably” render the claims indefinite because one cannot ascertain the metes and bounds of what is and what is not allowed. The examiner contends that the use of such preferences may lead to confusion over the intended scope of the claim. See MPEP § 2173.05(d).
Claim 59 (ii) recites the limitation “an isolated further binding molecule recited in claim 31”. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 31-39 and 41-59 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim 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 had possession of the claimed invention.
Claim 31 is drawn to an at least bispecific molecule comprising at least two first antigen binding sites and at least one second antigen binding site, wherein (i) the at least two first antigen binding sites is not a Fab, F(ab')2 or IgG; and (ii) the at least one second antigen binding site comprises a Fab, F(ab')2 or IgG.
Claim 32 limits the at least two antigen binding sites as two single chain scFvs.
However, the instant specification only discloses examples of a bispecific molecule that comprises one arm comprising two scFvs against CD28 and a second arm against a target antigen that is in an IgG format. The instant specification does not disclose other "non-Fab, non-F(ab')2, non-lgG" formats” for the at least first two antigen binding sites, such as a VHH. Additionally, other non-IgG formats are not disclosed for the at least one second antigen binding site.
It is well understood in the art that engineering functional bispecific antibodies is a complex process that is dependent on a multitude of factors, including the tertiary structure of the antibody. Therefore, substituting one type of antigen binding site with another, such as incorporating a VHH rather than an scFV, would not necessarily impart the same properties. For example, Brinkmann et al. (2017) teaches different antibody targets require a diverse panel of formats that may vary in size, arrangement, valencies, flexibility and geometry of their binding modules, as well as in their distribution and pharmacokinetic properties. In order to achieve bispecificity, factors that need to be taken into account include the special arrangement or size of the different target antigens, as well as, the target densities on cell surfaces. This determines which formats may be applicable to achieve bivalent, trivalent or multivalent binding to one or both antigens in a simultaneous or mutually exclusive manner. Small format variations, such as minor changes in linker length or composition or switch of domains, can be crucial determinants for functionality. Some design parameters may be deduced from structural models, however, in many cases suitable formats must be identified by generating and comparing the functionalities of different formats. Further, the more complex composition (e.g., 3–4 chains of bispecific antibodies in contrast to 2-chain IgGs) requires more extensive optimization of expression systems [pg. 202].
The instant application has not provided a sufficient description showing possession of the necessary 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 genus of bispecific molecules encompassing various structures, specificities and functions.
Given the large number of possible bispecific binding molecule formats, the skilled artisan would not have been in possession of the vast repertoire of at least bispecific binding molecules encompassed by the claimed invention; 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 genus of bispecific binding molecules, with the claimed specificity and functional attributes, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
The Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent
specification to “describe the claimed invention so that one skilled in the art can recognize what is
claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s
“disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter
purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir.
1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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 Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in
the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116).
Also, it is noted that the Court has held that the disclosure of screening assays and general
classes of compounds was not adequate to describe compounds having the desired activity: without
disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of
Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in
“possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support
need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein
v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —
i.e., what the written description and knowledge in the art would lead one to speculate as to
modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also
ensures that when a patent claims a genus by function, the specification recites sufficient materials to
accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broadly class of bispecific molecules, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Therefore, there is insufficient written description for the genus of binding molecules that are at least bispecific with the specific recited format encompassed by the claimed invention to provide sufficient structure for the bispecific binding molecules with the specific formats as claimed at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Claims 33-39 and 41-59 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claims and fail to clarify the issue.
Enablement
Claims 31-39 and 41-59 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for treating cancer in a subject; does not reasonably provide enablement for treating diseases as broadly claimed, or a disease associated with a pathogenic organism.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP § 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
Claim 31 is drawn to a method for the treatment of a disease in a subject comprising a binding molecule comprising at least two first antigen binding sites and at least one second antigen binding site, wherein (i) the at least two first antigen binding sites are not a Fab, F(ab')2 or IgG; and (ii) the at least one second antigen binding site comprises a Fab, F(ab')2 or IgG.
The claims are broad and inclusive of all types of diseases in humans generally. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible diseases represented by the terms “treatment of a disease in a subject”. There are over 10,000 distinct human diseases in existence, though the exact number depends on how one defines and categorizes them, particularly within rare diseases. Rare diseases alone constitute thousands of conditions, and when including common illnesses, injuries, and genetic conditions, the total is substantial. For instance, Espe (2018) teaches the MalaCards Human Disease Database arranges diseases in 2 distinct categories: anatomical and global. The anatomical disease section includes 18 major categories with more than 26,000 diseases representing all areas of the body, including blood, bone, immune, muscle, and reproductive diseases. The global disease section contains 6 categories: cancer, fetal, genetic, infectious, metabolic, and rare diseases, and almost 18,000 specific diseases [pg. 140, par. 2].
Claim 34 limits the antigenic target protein to a protein expressed on cells associated with a proliferative disorder, or a protein of other molecule associated with a pathogenic organism.
The claim is broad and inclusive of all types of pathogenic diseases in humans. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed.
Bartlett et al. (2022) teaches that there are 1,513 known species of human pathogens (bacteria, viruses, fungi, protozoa, and helminths) capable of causing disease in humans. Of these, approximately 13-15% are considered emerging or reemerging. While total pathogenic species are in the hundreds, these cause thousands of unique clinical diseases, with 16 million deaths occurring annually from infectious diseases [Introduction].
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
The state of the art teaches there is no known agent that can treat all types of diseases. The art of disease therapeutics involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific diseases with specific agents, there is no single therapeutic available for the treatment of diseases broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of any disease in a subject apart from cancer, with the claimed active ingredient makes practicing the claimed invention unpredictable.
Waite et al. (2020) teaches CD28 bispecific antibodies are engineered to activate T-cells by targeting CD28, aiming to treat solid tumors and blood cancers rather than all diseases generally. They work by binding to tumor-associated antigens (TAAs) and CD28, providing crucial costimulation for T-cell proliferation, often in combination with CD3 bispecifics or PD-1 inhibitors to enhance antitumor efficacy [Discussion, pg. 10].
Given the lack of predictability in treatment of diseases, one of skill in the art would have to engage in undue experimentation to first identify individuals to which the instant method would apply, and also to identify which CD28 bispecific that can treat the specific disease.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification sets forth in vitro examples providing a proof-of-concept for the instantly claimed CD28 bispecific antibody for the treatment of cancer. Specifically, CD28 bispecifics targeting proteins expressed in cancer cells (endoglin, B7-H3, FAP) induced activation of T cells within PBMC cultures in a target cell restricted manner [222-234]. However, none of the models demonstrate treatment of any other type of disease. One of skill in the art would be required to engage in extensive, difficult experimentation to identify the CD28 bispecific with the specific format recited in claim 31 that would possess the required functionality for each specific type of disease. This required experimentation is undue.
In conclusion, the claimed invention does not provide enablement for treatment of any disease, including diseases caused by pathogenic organisms. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 32-33, 35-39, and 41-59 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim.
Conclusion
No claim is allowed.
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571) 270-0730. The examiner can normally be reached Monday through Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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