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
Applicant’s election without traverse of Group I (claims 1-4, 6-9, 11-12, 19, and 21-22; species of anti-PD-L1 single chain antibody comprising CDR1 of amino acid sequence set forth in SEQ ID NO:2, CDR2 of amino acid sequence set forth in SEQ ID NO:7, and CDR3 of amino acid sequence set forth in SEQ ID NO:14) in the replies filed on 3/23/2026 and 6/15/2026 is acknowledged.
Claims 1-3, 6, 9, 11-12, 19, and 22 drawn to the elected invention are under consideration by the Examiner.
Claims 4, 7-8, 13, 15-17, and 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 5, 10, 14, and 18, have been canceled.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 8/20/2023 is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(a), written description
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.
4a. Claims 1-3, 6, 9, 11-12, 19, and 22, 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has claimed a fusion protein comprising an anti-PD-L1 single domain antibody, an anti-VEGF antibody, and a TGF-β binding fragment as recited in claim 1, the TGF-β binding fragment comprising a TGF-β RII extracellular region structural fragment. To support such a claim, the instant application discloses an anti-PD-L1 single domain antibody comprising CDR1 of amino acid sequence of SEQ ID NO: 2, CDR2 of amino acid sequence of SEQ ID NO: 7, CDR3 of amino acid sequence of SEQ ID NO: 14. There is no written description for an anti-PD-L1 single domain antibody of at least 90% sequence identity with SEQ ID NOs: 16-21 as recited in claim 6.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description 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.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002).
Further, recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
In the instant case, the specification discloses an anti-PD-L1 single domain antibody comprising CDR1 of amino acid sequence of SEQ ID NO: 2, CDR2 of amino acid sequence of SEQ ID NO: 7, CDR3 of amino acid sequence of SEQ ID NO: 14, but, no structure of variants of this antibody having 90% sequence identity to one of SEQ ID Nos: 16-21 as set forth in claim 6 have been described. Furthermore, no structure of variants of CDR1, CDR2, CDR3, comprising the amino acid sequences set forth in any one of SEQ ID NO: 2, 7, and 14, respectively, have been described. As such, the structure required of an antibody as set forth in claim 1, such that it has all of the functions recited in the independent claim is not disclosed in the specification as filed. Applicant is reminded that the courts have long ruled that “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. 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody does not provide evidence of possession of the antibody itself.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the three different complementarity determining regions, heavy chain CDR 1, 2 and 3 (in this application for the anti-PD-L1 single domain antibody fragment), which provide the majority of the contact residues for the binding of the antibody to its target epitope, and the 6CDRs for the anti-VEGF antibody. The amino acid sequences and conformations of each of the CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin (Janeway et al., 1997, see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., 1982, see entire document, particularly the abstract and the middle of the left column of page 1982). As discussed above, only an anti-PD-L1 single domain antibody comprising CDR1 of amino acid sequence of SEQ ID NO: 2, CDR2 of amino acid sequence of SEQ ID NO: 7, CDR3 of amino acid sequence of SEQ ID NO: 14, respectively, has been described.
Indeed, in AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) the court ruled that all of the antibodies disclosed by AbbVie were all structurally similar as they were variants of a starting antibody named Joe9 and therefore did not serve to inform artisans as to the breadth of structures which had the recited function of cytokine binding. In the instant application, the instant claims recite antibodies to be used in the claimed methods while the specification does not disclose structures which necessarily have the requisite functions. The instant specification fails to disclose sufficient structural information to indicate to artisans that Applicant had possession of the anti-PD-L1 single domain antibodies, and the anti-VEGF antibody as presently claimed in claim 1. Therefore, the broad genus of antibodies recited in Applicant’s claimed product lacks adequate written description because there does not appear to be sufficient correlation between the structure of the antibodies in question and their recited functional activities. As such a skilled artisan would reasonably conclude that Applicant was not in possession of the recited genus of antibodies in the claimed fusion protein recited in claim 1, and thus logically could not be in possession of such antibodies at the time the instant application was filed. Therefore, there is insufficient written description for the genus of antibodies having the claimed “limitations” at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 USC 112(a). Applicant has claimed a genus of antibodies that are recited as binding to PD-L1 and VEGF, but have not provided a written description of the anti-PD-L1 single domain antibodies and VEGF antibodies claimed.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
As set forth in Amgen v. Sanofi, knowing the structure of what is being bound does not provide knowledge of the structure of the antibody that is being claimed. It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”. Thus, the claims lack adequate written description for the claimed antibody as they simply fail to recite what the antibody is (i.e. its sequence/structure).
The claims recite a fusion protein which combines the function of an anti-PDL1 monoclonal antibody, an anti-VEGF monoclonal antibody, and a TGF-β receptor, where the anti-PDL1 monoclonal antibody blocks the PD-L1/PD-1 interaction, the anti-VEGF monoclonal antibody inhibits microvascular growth and tumor metastasis, and the TGF-β receptor alleviates the abnormal T cell functions caused by TGF-β in the tumor microenvironment and enhances immune response, the fusion protein molecule having an excellent tumor suppression effect, without reciting the specific amino acid sequences of the antibodies or the sequence of the TGF-β receptor in claim 1 (See [0024] on page 4). The breadth of claim 1 is expanded further because it allows for one or more mutations in the CDR sequences of the anti-PD-L1 single domain antibody, and VEGF antibodies, as compared to the wild-type antibodies, and could be from more than one antibody clone.
It is well established in the art that, for the VEGF antibody for example, that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope.
As has already been stated above, the instant specification does not provide any mutagenesis data concerning how disclosed CDR sequences can be mutated and maintain binding at the single amino acid level, by swapping CDR sequences, or by doing both simultaneously. Thus, there does not appear to be any reasonable disclosure of how the CDR sequences of the lead clones can be mutated and/or mixed and matched while maintain the function of antigen binding. Note that given that alterations as small as a single amino acid residue change can abrogate binding as set forth by Rudikoff et al., completely random CDR sequences which also can additionally comprise one or more point mutations within the paucity of specific structure which is required to be present does not reasonably appear to be correlated with maintenance of the function of antigen binding.
It should also be noted that data showing that, for example, an isolated polypeptide consisting of a single CDR sequence maintains binding to antigen has not been provided. Thus, artisans would reasonably expect that only VEGF antibodies which have six fully defined CDR sequences obtained from the same lead clone will maintain the recited function of antigen binding based upon the data presented in the instant specification.
Therefore, it appears that for the broad genus of antibodies that bind PD-L1 and VEGF claimed by Applicant lacks adequate written description because there does not appear to be sufficient correlation between the structure of the claimed antibodies and the function. As such, a skilled artisan would reasonably conclude that Applicant was not in possession of the claimed fusion protein comprising the genus of antibodies at the time the instant application was filed.
Claim 1 recites “a TGF-β binding fragment”. The claims, however, do not require that the “a TGF-β binding fragment” recited in claim 1 possess any particular conserved structure, or other distinguishing feature.
To provide adequate written description and evidence of possession of a 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, and any combination thereof. In this case, the only factor present in the claim that is sufficiently disclosed is a recitation of a desired activity. The specification does not identify any particular portion of the structure, nor does it provide a disclosure of structure/function correlation. The distinguishing characteristics of the claimed genus for the antigens or the targeting means are not described. Accordingly, the specification does not provide adequate written description of the claimed genus of antigens or targeting means.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 [10 USPQ2d 1614] (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”). Thus, an applicant complies with the written-description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572.
See University of Rochester v. G.D. Searle & Co., 68 USPQ2d 1424 (DC WNY 2003) and University of Rochester v. G.D. Searle & Co. et al. CAFC [(03-1304) 13 February 2004]. In University of Rochester v. G.D. Searle & Co. a patent directed to method for inhibiting prostaglandin synthesis in human host using an unspecified compound, in order to relieve pain without side effect of stomach irritation, did not satisfy written description requirement of 35 U.S.C. §112, since the patent described the compound's desired function of reducing activity of the enzyme PGHS-2 without adversely affecting PGHS-1 enzyme activity, but did not identify said compound, since invention consists of performing “assays” to screen compounds in order to discover those with desired effect. The patent did not name even one compound that assays would identify as suitable for practice of invention, or provide information such that one skilled in art could identify suitable compound. And since specification did not indicate that compounds are available in public depository, the claimed treatment method cannot be practiced without compound. Thus the inventors cannot be said to have “possessed” claimed invention without knowing of a compound or method certain to produce compound. Thus said patent constituted an invitation to experiment to first identify, then characterize, and then use a therapeutic a class of compound defined only by their desired properties.
Therefore the full breadth of the claims fails to meet the written description provision of 35 U.S.C. §112, first paragraph. In the instant case, for example, Applicants have failed to describe which “TGF-β binding fragment” has the desired property. 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.
Claim Rejections - 35 USC § 112(a), scope of enablement
4b. Claims 1-3, 6, 9, 11-12, 19, and 22 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 a fusion protein comprising an anti-PD-L1 single domain antibody fragment comprising CDR1 comprising the amino acid sequence of SEQ ID NO: 2, CDR2 has the amino acid sequence of SEQ ID NO: 7, and CDR3 has the amino acid sequence of SEQ ID NO: 14;, an anti-VEGF fragment comprising SEQ ID NO:23, and a TGF-β binding fragment comprising SEQ ID NO:24, does not reasonably provide enablement for an antibody as recited in claim 1. 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.
Instant claim 1 encompasses antibody variants with amino acid substitutions in the heavy chain CDR1, CDR2 and CDR3 of an anti-PD-L1 single domain antibody fragment. Thus, these claims encompass variant antibodies, while the specification only discloses an antibody which comprises H-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, H-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, H-CDR3 comprising the amino acid sequence of SEQ ID NO: 14.
Claim 1 recites “a fusion protein, comprising an anti-PD-L1 single domain antibody fragment, an anti-VEGF fragment, and a TGF-β binding fragment”.
There is insufficient guidance and direction as to make and use all the encompassed fusion proteins that are encompassed by the scope of the claim. Additionally, the instant specification only discloses a TGF-β binding fragment which is a TGF-β RII extracellular region structural fragment comprising the amino acid sequence set forth in SEQ ID NO:24. The genus encompasses variant anti-PD-L1 single domain antibodies, and anti-VEGF antibodies, that comprise disparate amino acid sequences, including numerous differences in linear and conformational epitopes. The specification does not provide sufficient guidance as to which of the amino acids, for example, of the heavy chain CDR1, CDR2, CDR3 of an anti-PD-L1 single domain antibody, may be changed while structural or functional activity and specificity of the antibody is retained. For example, Lederman et al. disclose that a single amino acid substitution in a common allele ablates binding of a monoclonal antibody (See abstract). Li et al. also disclose that dissociation of immunoreactivity from other biological activities when constructing analogs (See entire document). Because of this lack of guidance, the extended experimentation that would be required to determine which modifications would be acceptable to retain structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable it would require an undue amount of experimentation for one of skill in the art to arrive at the claimed invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112(a), have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states on page 1404:
"Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They 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. The nature of the invention is a method of using engineered antibodies and immunotherapy where the relative level of skill of those in the art is deemed to be high. In view of the lack of the predictability of the art to which the invention pertains as evidenced by the Lederman et al and Li et al references, the lack of guidance and direction provided by applicant, and the absence of working examples, undue experimentation would be required to make and use the claimed antibodies with no reasonable expectation of success, commensurate in scope with the claimed invention.
The claims are overly broad because no guidance is provided as to which of the myriad of antibodies in the fusion protein encompassed by the claims will retain the characteristics of the desired fusion protein. No actual or prophetic examples on expected performance parameters of any of the possible variants of the claimed, for example, anti-PD-L1 single domain antibody molecule have been disclosed except for an antibody, which comprises H-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, H-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, H-CDR3 comprising the amino acid sequence of SEQ ID NO: 14. Furthermore, it is known in the art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein's function.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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. 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 Vol 79 page 1979). Rudikoff et al. teach 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. It is unlikely that an antibody as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of a VEGF antibody in unspecified order have the required binding function. The specification provides no direction or guidance regarding how to produce antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone.
As evidenced by Adair et al. (US Patent 6,632,927) transfer of CDR regions alone are often not sufficient to provide satisfactory binding activity in the CDR-grafted product (col.2 lines 58-61). Panka et al (Proc. Natl. Acad. Sci. USA Vol 85, 3080-3084, 5/88) demonstrate that a single amino acid substitution of serine for alanine results in decreased affinity. In at least one case it is well known that an amino acid residue in the framework region is involved in antigen binding (Amit et al, Science Vol 233, 747-753, 1986). One of skill in the art would neither expect nor predict the appropriate functioning of the antibody as broadly as is claimed. It is suggested that the specific CDR regions of both the heavy and light chain of the VEGF antibody be explicitly recited within the claim. Therefore, in view of the lack of guidance in the specification and in view of the discussion above one of skill in the art would be required to perform undue experimentation in order to make and use the claimed invention.
Applicant has claimed a genus of VEGF antibodies which are required to have specific CDR sequences recited by SEQ ID NO. The only reasonable way to make an antibody that is guaranteed to have a specific sequence or sequences are required by the instant claims, is to use the techniques of recombinant molecular biology. It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR 1,2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982).
As stated above the antibody sequences which are not fixed by the instant claim language can be effectively random and thus there does not appear to be any predictability as to which sequences will or will not maintain antigen binding activity except for those which have six fully defined non-degenerate CDR sequences, three in the VH and three in the VL. Thus, there is no disclosed data which would reasonably allow artisans to make the full breadth of what is encompassed by the instant claim language.
Therefore, in view of the breadth of the instant claimed invention, the guidance and direction of the instant specification and the teachings of the art, artisans would be unable to make and use the full breadth of Applicant’s genus of fusion proteins comprising anti-PD-L1 single chain antibodies, a VEGF antibody and a TGF-β binding fragment, as presently claimed without first performing extensive unpredictable basic research and experimentation.
Claim rejections-35 USC § 112(b)
5. 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.
5a. Claims 1-3, 6, 9, 11-12, 19, and 22 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 pre-AIA the applicant regards as the invention.
Claim 1, line 2, is vague and indefinite because it recites “a TGF-β binding fragment”. It is unclear if this fragment is an antibody, or TGF-β receptor extracellular region, or something else. To overcome this rejection, the claim must be amended to recite the specific “TGF-β binding fragment” and its structure, for which there is a basis in the instant specification.
Claim 3, lines 12-13, is vague and indefinite because it recites “CDR1 has an amino acid sequence of SEQ ID NO: 2, CDR2 has an amino acid sequence of SEQ ID NO: 7, and CDR3 has an amino acid sequence of SEQ ID NO: 14” rather than the correct “CDR1 comprises the amino acid sequence of SEQ ID NO: 2, CDR2 comprises the amino acid sequence of SEQ ID NO: 7, and CDR3 comprises the amino acid sequence of SEQ ID NO: 14”. Appropriate correction of the claim is required to obviate this rejection.
Claim 6 is vague and indefinite for several reasons.
Claim 6, line 5, is vague and indefinite because it recites “sharing at least” rather than “having at least ”.
Furthermore, claim 6, lines 6-7, is vague and indefinite because it recites “and a function of the polypeptide fragment in a)”. It is unclear what the function being recited in the claim is.
Claim 6, lines 9-10, is vague and indefinite because it recites “….antibody fragment is derived from Vicugna pacos” which is confusing because the metes and bounds of the term “derived” are unclear. Does the anti-PD-L1 single domain antibody have “50%” or “60%” or even 70% similarity to the parent antibody and how is the claimed antibody derived from Vicugna pacos?
Furthermore, the recitation of “and/or” in claim 6, line 8, is confusing because it is unclear if the anti-PD-L1 single domain antibody fragment must possess limitations 6(a) and 6(b). Therefore, the metes and bounds of the claim are unclear.
Claim 9 is vague and indefinite for several reasons.
Claim 9, lines 3-4, are rejected as vague and indefinite because of the recitation of “preferably” and “more preferably” because it is unclear what specifically is encompassed and not encompassed by the claim. The limitations “preferably” and “more preferably” must be deleted from the claim to obviate this rejection.
Furthermore, the recitation of “and/or” in claim 9, lines 3, and 5, is confusing because it is unclear if the linker must possess the limitations recited in the claim. Therefore, the metes and bounds of the claim are unclear.
In addition, claim 9, lines 3-6, is vague and indefinite because it recites “the linker peptide fragment is rich in G, S, and/or A, more preferably, the linker peptide fragment is a flexible polypeptide chain consisting of G glycine and/or S serine and/or A alanine, wherein a length of the amino acid sequence of the linker peptide fragment is 3-30”. It is unclear why “G, S, and/or A”, the single letter amino acid code is recited in line 3, and “G glycine and/or S serine and/or A alanine”, the single letter amino acid code and the full name are spelled out in line 5. Appropriate correction of the claim is required, for consistency, to obviate this rejection.
Claim 11 is vague and indefinite for several reasons.
The recitation of “and/or” in claim 11, lines 4, 6, and 8, is confusing because it is unclear if the fusion protein must possess the limitations recited in the claim. Therefore, the metes and bounds of the claim are unclear.
Claim 11, line 8, is vague and indefinite because it recites “a TGF-β binding fragment”. It is unclear if this fragment is an antibody, or TGF-β receptor extracellular region, or something else. To overcome this rejection, the claim must be amended to recite the specific “TGF-β binding fragment” and its structure, for which there is a basis in the instant specification.
Claim 12 is confusing because it is unclear what the SEQ ID NOs recited in the claim refer to. Is SEQ ID NO:23 the anti-VEGF fragment? What do SEQ ID NOs: 25-33 refer to? The claim must be amended to recite these specific limitations to obviate this rejection.
Claim 22 is vague and indefinite for several reasons.
The recitation of “and/or” in claim 22, lines 4, and 6, is confusing because it is unclear if the fusion protein must possess the limitations recited in the claim. Therefore, the metes and bounds of the claim are unclear. The recitation of “and/or” does not refer to SEQ ID NOs: 34-36, and therefore, these SEQ ID NOs limitations are not present in the first and second linker peptide fragments.
Claim 22, line 7, is vague and indefinite because it recites “a TGF-β binding fragment”. It is unclear if this fragment is an antibody, or TGF-β receptor extracellular region, or something else. To overcome this rejection, the claim must be amended to recite the specific “TGF-β binding fragment” and its structure, for which there is a basis in the instant specification.
Claims 2, and 19 are vague and indefinite insofar as they depend on the above rejected claims for their limitations.
Claim rejections-35 U.S.C. 103
6. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
6a. Claims 1, 9, 11, 19, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020006511-Al in view of Broos et al (2019).
The claims of the instant invention are directed to a fusion protein, comprising an anti-PD-L1 single domain antibody fragment, an anti-VEGF fragment, and a TGF-3 binding fragment.
WO2020006511-Al discloses a pharmaceutical composition for treating cellular proliferative diseases, comprising a trispecific antagonist comprising: an immunoglobulin scaffold comprising a CHI domain, a CH2 domain, and a CH3 domain; a first targeting domain comprising one or more anti-PD-1 variable region domains or one or more anti PD-Ll variable region domains; a second targeting domain comprising a component of VEGFR (equivalent to an antagonistic VEGF fragment); and a third targeting domain comprising a TGF-beta pathway inhibitor, the second targeting domain comprises the amino acid sequence of SEQ ID NO: 185, and the third targeting domain comprises a TGFβ1 RII extracellular domain (ECD), the first targeting domain is structurally linked to the amino terminus of the immunoglobulin scaffold via a peptide linker, and the peptide linker comprises an amino acid sequence selected from SEQ ID NOs: 284-289, the second targeting domain is structurally linked to the carboxyl terminus of the immunoglobulin scaffold via a peptide linker, and the peptide linker comprises an amino acid sequence selected from SEQ ID NOs: 284-289, the third targeting domain is linked to the carboxyl terminus of the second targeting domain via a peptide linker, and the peptide linker comprises an amino acid sequence selected from SEQ ID NOs: 284-289 (See page 64-65, [260-261]; claims 16-32). The reference is silent with respect to the limitation, the fusion protein comprises “an anti PD-Ll single-domain antibody fragment”.
Broos et al (2019) discloses that PD-L1 single domain antibodies (sdAbs) have high affinity for PD-L1, are smaller in size so the sdAbs can penetrate tumors more easily, and have high affinity for PD-L1 for desirable PD-1:PD-L1 blocking activity (See abstract; page 8, Figure 6).
Therefore, it would have been obvious to one of ordinary skill in the art, at the time the instant invention was conceived, to modify the fusion protein as disclosed by WO2020006511-Al and substitute the PD-L1 antibody with the PD-L1 sdAbs disclosed by Broos because Broos et al teaches that PD-L1 single domain antibodies (sdAbs) have high affinity for PD-L1, are smaller in size so the sdAbs can penetrate tumors more easily, and have high affinity for PD-L1 for desirable PD-1:PD-L1 blocking activity. Therefore, Broos et al provides the motivation and expectation of success to substitute in the fusion protein disclosed by WO2020006511-Al, the PD-L1 sdAb disclosed by Broos et al , which PD-L1 sdAb provides higher specificity for PD-L1.
Therefore, the combination of references renders obvious claims 1, 9, 11, 19, and 22 in the absence of evidence to the contrary.
Conclusion
No claim is allowable.
Claims 1-3, 6, 9, 11-12, 19, and 22 are rejected.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PREMA MARIA MERTZ whose telephone number is (571)272-0876. The examiner can normally be reached on Monday to Thursday from 7:30am to 6:00pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, VANESSA FORD, can be reached at telephone number 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
/PREMA M MERTZ/ Primary Examiner, Art Unit 1674
Prosecution Insights