DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed December 1, 2025 is pending.
Claims 3-7, 9, 11-13, 16-21, 23, 24, 26-28, 30-34, 36-41, 43-47, 49, 50, 52-55, 57-70, 72, 74-78, 82, 83, 85, 87, 88, 90, 94, and 98 are canceled.
Claims 1, 2, 8, 10, 14, 15, 22, 25, 29, 35, 42, 48, 51, 56, 71, 73, 79-81, 84, 86, 89, 91-93, and 95-97 are pending.
Claims 1, 86, and 89 are independent claims.
Applicant’s election without traverse of Group I (claims 1, 2, 8, 10, 14, 15, 22, 25, 29, 35, 42, 48, 51, 56, 71, 73, 79-81, 84, 86, 89, and 97, drawn to fusion proteins and a kit); and the species of PD-1-PDL1 as the ligand-receptor pair, a linker comprising a protease cleavage site, one of the first and second linkers comprises a protease cleavage site, uPA as the protease, and an antigen that is expressed on an immune cell in the reply filed on December 1, 2025 is acknowledged.
Claims 48, 51, 56, 91-93, 95, and 96 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1, 2, 8, 10, 14, 15, 22, 25, 29, 35, 42, 71, 73, 79-81, 84, 86, 89, and 97 are currently under consideration.
Nucleotide and/or Amino Acid Sequence Disclosures
The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. The incorporation by reference paragraph to the sequence listing recites the incorrect file creation date. The paragraph should recite: “The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, generated on January 20, 2023, is named 18017319_1_1.TXT, and is 325,031 bytes in size.”
Required response - Applicant must:
• 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.
The examiner has also noted that the amino acid sequences "EAAAK require sequence identifiers since they are four or more amino acids in length.
Priority
The instant Application is a 371 of PCT/CA2021/051006 filed 07/20/2021 and claims domestic benefit to provisional applications 63/172,626 filed 04/08/2021 and 63/054,180 filed 07/20/2020.
Specification
The instant application appears to be in sequence compliance for patent applications containing nucleotide sequence and/or amino acid sequence disclosures, except for the following:
It does not appear that all of the sequences disclosed in the specification as filed are provided with the appropriate SEQ ID NOs. in compliance with the Sequence rules as set forth in 37 CFR 1.821(d).
For example, the instant specification does not appear to have SEQ ID NOs. for the amino acid sequences "EAAAK," "PPPP," "GPPPG," "GGPPPGG," "GPPPPG," and "GGPPPPGG" in [0024]. These sequences require sequence identifiers since they are four or more amino acids in length.
Applicant is required to review the entire instant application for compliance with the Sequence Rules.
Claim Objections
Claim 29 is objected to because of the following informalities:
Claim 29 recites “(GlynSer)” and variations thereof wherein the “n” or the number is meant to be a subscript. The terms should instead be “(GlynSer).”
Claim 29 also recites “GPPPG. GGPPPGG, GPPPPG or GGPPPPGG” in line 8 with a period after the first sequence that should be a comma. The claim should recite: “GPPPG, GGPPPGG, GPPPPG or GGPPPPGG.”
Claim 29 also recites the amino acid sequences "EAAAK These sequences require sequence identifiers since they are four or more amino acids in length.
Claim Rejections - 35 USC § 112
Indefinite Language
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, 2, 8, 10, 14, 15, 22, 25, 29, 35, 42, 71, 73, 79-81, 84, and 97 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.
Claims 1, 8, 15, 25, 29, 73, and 81 recite the phrase "optionally" rendering the claims indefinite because it is unclear whether the limitation(s) following the phrase is part of the claimed invention. See MPEP § 2173.05(d).
Claim 1 recites “and optionally at least one of the first and second peptidic linkers comprises a protease cleavage site” in line 12.
Claim 8 recites “optionally a heterodimeric Fc” in line 2.
Claim 15 recites “and optionally:(a) the ligand PDL1 comprises an amino acid sequence according to SEQ ID NO: 8, and/or (b) the receptor PD1 comprises an amino acid sequence according to SEQ ID NO: 9” in lines 2-5 and “and optionally (a) the ligand CD80 comprises an amino acid sequence according to SEQ ID NO: 25,SEQ ID NO: 185, SEQ ID NO: 187 or SEQ ID NO: 189, and/or (b) the receptor CTLA4 comprises an amino acid sequence according to SEQ ID NO: 26” in lines 6-10.
Claim 25 recites “optionally wherein the protease is uPA or matriptase” in line 10.
Claim 29 recites “optionally PPP or PPPP, or a glycine-proline linker, optionally GPPPG, GGPPPGG, GPPPPG, or GGPPPPGG” in lines 7 and 8.
Claim 73 recites “and optionally at least one of the ligand or the receptor in the ligand-receptor pair is capable of binding to an immunomodulatory target” in lines 7 and 8.
Claim 81 recites “optionally wherein (a) one antigen is an antigen expressed by T cells and the other antigen is an antigen expressed by cancer cells, optionally wherein the antigen expressed by T cells is CD3 or (b) one antigen is CD3 and the other antigen is HER2” in lines 2-4.
It is noted that for the purpose of applying prior art, any limitations following an optionally clause have not been considered.
Claim 1 also recites “the first and second peptidic linkers are of sufficient length to allow pairing of the ligand and receptor” in lines 11 and 12. It is noted that the phrase “sufficient length” has not been defined by the Applicant nor is it obvious to one or ordinary skill in the art. While the “sufficient length” must “allow pairing of the ligand and receptor,” the applicant has not defined any structural elements that make up this “sufficient length,” namely, the minimum and maximum number of amino acid sequences at the very least. Therefore, it is unclear what “sufficient length” actually means.
Claim 2 recites “or (b) the biologically functional protein comprises or consists of a polypeptide scaffold” in line 4. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 2 recites the broad recitation “comprises a polypeptide scaffold”, and the claim also recites “consists of a polypeptide scaffold” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 22 recites “the ligand or the receptor is engineered to comprise one or more additional protease cleavage sites” in lines 6 and 7. The phrase “additional protease cleavage sites” lacks antecedent basis because claim 22 is dependent on claim 1 which only recites “a protease cleavage site” in the optionally clause. It is unclear whether the phrase “a protease cleavage site” is part of the invention of claim 1 (see above). Therefore, if it is unclear if a first protease cleavage site is present in the fusion protein and therefore how there could be additional protease cleavage sites if there isn’t one to begin with.
Claim 29 also recites “wherein the peptidic linker” in line 1. Claim 29 is dependent on claim 1 which recites that there are two peptidic linkers, a first and a second. Therefore, there is no antecedent basis for the phrase “the peptidic linker” in claim 29 because it is unclear which linker in claim 1 is being referred to.
Claim 97 recites “A kit comprising at least one polypeptide of the fusion protein of claim 1” in line 1. Claim 97 is dependent on claim 1 which is drawn to a fusion protein comprising a biologically functional protein, wherein the biologically functional protein comprises at least a first polypeptide and a second polypeptide. Thus, as claim 97 currently reads, only one of the polypeptides of the biologically functional protein of the fusion protein are required to be comprised in the kit. It is unclear if claim 97 is really intended to be drawn to a kit comprising only one polypeptide of the fusion protein of claim 1 or if it is meant to be drawn to the entire fusion protein of claim 1.
Written Description
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, 8, 10, 14, 15, 22, 25, 29, 35, 42, 71, 73, 79-81, 84, 86, 89, and 97 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 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.
The instant claims are drawn to fusion proteins comprising: a biologically functional protein, a ligand-receptor pair, a first peptidic linker and a second peptidic linker; wherein the biologically functional protein comprises at least a first polypeptide and a second polypeptide; and the ligand-receptor pair comprises an extracellular portion of an immunoglobulin superfamily receptor and its cognate ligand or a receptor-binding fragment thereof; wherein the ligand is fused to a terminus of the first polypeptide via the first peptidic linker; the receptor is fused to the same respective terminus of the second polypeptide via the second peptidic linker; and the first and second peptidic linkers are of sufficient length to allow pairing of the ligand and receptor; and a kit comprising one of the fusion proteins.
Figure 1(A), copied below, depicts a fusion protein wherein by fusing PD-1 (checkered) and PD-L1 (striped) to the N-termini of the heavy and light chain of an antibody, respectively, the antigen binding site of the Fab (grey) can be sterically blocked (or masked) by the Ig superfamily heterodimer that is formed between PD-1 and PD-L1 (e.g. see [0030]). Upon removal of one side of this mask via proteolytic cleavage (bolt) of one of the linkers that is introduced between the masking domain and the Fab by a tumor microenvironment (TME)-specific protease, part of the mask can be released and binding by the Fab to its target can be restored. Furthermore, the part of the mask that remains covalently attached to the Fab adds functionality by binding to its immunomodulatory partner, such as PD-1 or PD-L1 (e.g. see [0030]). It is noted that the fusion proteins are masked to decrease any on-target off-tissue (e.g., off-tumor) action (i.e., toxicity) associated with target engagements (e.g. see [0087]).
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Instant Figure 1(A)
The Applicant discloses 23 fusion protein constructs as N-terminally masked antibodies or fragments thereof that comprise all of the elements recited in claim 1: variant Nos. 30423, 30426, 30430, 30436, 31934, 31722, 31723, 31728, 31729, 31736, 31737, 31732, 31733, 28647, 28662, 30444, 33525, 33526, 33527, ZW Fc1, 32478, 32479, and 34164 (e.g. see Tables A, C, and F-I).
Figures 1(A)-(C) depict fusion proteins of the instant invention which comprise tumor microenvironment (TME)-specific protease cleavable or uncleavable linkers introduced between the masking domain and the antigen-binding domains. See claim interpretation above.
It is noted that variant Nos. 30423, 30426, 31722, 31728, 31736, 31732, 28647, 28662, and 32478 comprise uncleavable peptidic linkers; variant Nos. 30430, 30436, 31723, 31729, 31737, 31733, 30444, 33525, 33526, 33527, ZW Fc1, and 32479 comprise one protease cleavable peptidic linker and one uncleavable peptidic linker; and variant Nos. 31934 and 34164 comprise two protease cleavable peptidic linkers (e.g. see Tables A, C, and F-I).
When given the broadest reasonable interpretation in light of specification, the fusion proteins of the instant invention are defined broadly to be any fusion protein that comprises any biologically functional protein, a ligand-receptor pair, any first peptidic linker and any second peptidic linker, wherein the ligand is fused to either terminus of the first polypeptide via the first peptidic linker; the receptor is fused to the same respective terminus of the second polypeptide via the second peptidic linker.
It is noted that the broadest claim (claim 1) does not indicate any specific biologically functional proteins or any specific linker structure for the genus of fusion proteins as claimed.
Claim 2 limits the biologically functional protein to a polypeptide scaffold.
Claims 8, 86, and 89 limit the polypeptide scaffold to a polypeptide scaffold that comprises a dimeric Fc region.
Claim 22 limits at least one of the peptidic linkers to a protease cleavable linker.
Claim 29 limits the linkers to (GlynSer), (EAAAK)n, polyproline, glycine-proline linkers, linkers that comprise SEQ ID NO: 38 or 28, or linkers that comprise an immunoglobulin hinge region sequence comprising an amino acid sequence having up to a 30 percent difference in amino acid sequence identity compared to a wildtype immunoglobulin hinge region amino acid sequence.
Claim 35 limits the biologically functional proteins to those that comprise a VH and VL domain that form a first antigen binding site.
Claims 73 and 89 further limit the biologically functional proteins of claim 35 to those wherein the first antigen binding domain is a Fab.
Claim 79 further limits the biologically functional proteins of claim 35 to those that comprise a second antigen binding domain comprising a second VH and VL pair.
Claim 80 further limits the fusion protein of claim 79 to those that comprise a second ligand-receptor mask that is attached to the second antigen binding domain via third and fourth peptidic linkers wherein at least one of the third and fourth linkers comprise a protease cleavage site.
Claim 81 limits the biologically functional proteins of claim 79 to a bispecific, i.e. binds two distinct antigens.
Claim 84 limits the bispecific proteins to those that bind CD3 and comprise the recited CDRs.
It is noted that no claim recites the complete structure of the linker and only claims 8, 35, 42, 71, 73, 79-81, 84, 86, and 89 recite sufficient structure for the biologically functional protein.
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 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.”
Autio et al. (Clin Cancer Res. 26(5): 984-989) teach that a class of recombinant, proteolytically activated antibody prodrugs called Probody therapeutics, which exploit the hallmark dysregulation of protease activity in tumors and are designed to largely restrict drug activity to the tumor microenvironment (TME) (e.g. see page 986, left column, first paragraph under “Probody Therapeutics”). A Probody therapeutic consists of three modular components—an active anticancer monoclonal IgG antibody or fragment of a variable region, a masking peptide linked to the N-terminus of the light chain, and a protease-cleavable substrate linker peptide—produced as a single (or fusion) protein using recombinant antibody production methodology. In healthy tissue, the Probody therapy remains largely intact and blocked from target binding and retains the long circulatory half-life expected for mAb therapies. When a Probody therapeutic reaches the TME, tumor-associated proteases cleave the substrate linker, which releases the mask, enabling the antibody to bind target antigen (e.g. see page 986, left column, first paragraph under “Probody Therapeutics”).
Lin et al. 2020 (J. Biomed. Sci. 27(76); 1-20, an IDS reference filed 08/07/2023) more specifically discuss the importance of the linker structure in a pro-antibody. Lin et al. teach that in order to optimize the masking efficiency, adjusting the linker sequence between the mask and the antibody by amino acid addition, deletion or substitution, and combining with structure-based computational simulation may assist scientists in rationally predicting and adjusting the length or bending angle of the connecting linker and optimizing the coverage rate of different masks to obtain the highest masking efficiency for various antibodies (e.g. see page 13, paragraph spanning left and right columns).
Thus, the art ultimately teaches that the linker in these masked fusion proteins must be on the N-terminus of the antibody, comprise a protease cleavable site, and must be of appropriate length and stability in order to allow for (1) efficient masking of the underlying antibody or fragment thereof and (2) efficient unmasking in order to activate the underlying antibody or antigen binding fragment thereof by allowing for antigen binding once in the tumor microenvironment.
Furthermore, the length, flexibility, and protease substrate composition of the peptidic linkers of the instant invention appear to be even more important than those for a pro-antibody. The mask in a pro-antibody as described by Autio et al. and Lin et al. are intended to be fully shed from the fusion protein upon cleavage by a TME-associated protease. In contrast, only one of the masks in the of fusion proteins of the instant invention are intended to be shed while the other is meant provide a biological function in addition to the antigen-binding function of the underlying antibody.
Thus, given that the fusion proteins of the instant invention are intended to be masked by a receptor-ligand pair that is meant to have only one component (receptor or ligand) cleaved from the fusion protein once in the TME so that the other component remains covalently attached to the Fab and adds functionality by binding to its immunomodulatory partner, such as PD-1 or PD-L1; the peptidic linkers of the instant invention must not only be of appropriate length and flexibility to permit masking but also to permit the antigen-binding domain to bind its target while the receptor or ligand is still covalently attached and to also allow the receptor or ligand to bind its immunomodulatory partner.
As noted above, the Applicant has disclosed 23 fusion protein constructs as N-terminally masked antibodies or fragments thereof that comprise all of the elements recited in claim 1. Twelve of these constructs comprise one protease cleavable peptidic linker and one uncleavable peptidic linker to permit release of one component of the receptor-ligand pair while allowing the other component to remain covalently attached to the fusion protein and free to bind its immunomodulatory partner. Nine of these constructs comprise only non-cleavable peptidic linkers so that antibody cannot be unmasked and two of these constructs comprise two protease cleavable peptidic linkers so that the receptor-ligand mask can be fully shed and neither the receptor or ligand remains attached to the fusion protein and therefore cannot bind its immunomodulatory partner.
Such a disclosure does not serve to provide sufficient written description of the claimed genus of fusion proteins that comprises any biologically functional protein, a ligand-receptor pair, any first peptidic linker and any second peptidic linker, wherein the ligand is fused to either terminus of the first polypeptide via the first peptidic linker; the receptor is fused to the same respective terminus of the second polypeptide via the second peptidic linker.
The disclosure does not identify any specific structural features or combination of features which give rise to (1) peptidic linkers that are of sufficient length to allow pairing of the ligand and receptor or (2) a protein with any biological function. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited peptidic linkers or biologically functional proteins which gives rise to their functional activity. Ultimately, identifying: (1) peptidic linkers simply on the basis of being of sufficient length to allow pairing of the ligand and receptor or (2) a protein simply on the basis of having a biological function; rather than by identifying the sequence/structure of the peptidic linkers and the biologically functional protein in question is generally insufficient to provide written description.
Thus, there is insufficient written description for the breadth of fusion proteins comprising any biologically functional protein, a ligand-receptor pair, any first peptidic linker and any second peptidic linker, wherein the ligand is fused to either terminus of the first polypeptide via the first peptidic linker; the receptor is fused to the same respective terminus of the second polypeptide via the second peptidic linker.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of fusion proteins encompassed by the claims at the time the instant application was filed.
Amending claim 1 to recite: (1) that the biologically functional proteins are antibodies or fragments thereof; (2) that the peptidic linkers are attached to the N-termini of the polypeptides; and (3) specific amino acid sequences for the peptidic linkers would obviate this part of the rejection.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 8, 22, 25, 29, 86, and 97 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Preyer et al. 2020 (WO2020131697, an IDS reference filed 08/07/2023).
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Preyer et al. 2020 (WO2020131697, an IDS reference filed 08/07/2023) teach Twin Immune Cell Engagers (TWICE) comprising a first component and second component (e.g. see Abstract). Each component comprises a targeting moiety that binds a tumor antigen expressed by a cancer or an antigen expressed by a non-cancer cell in the tumor microenvironment (e.g. see Abstract). The two components may be present in two separate polypeptides or in a single polypeptide (e.g. see [00104]). Figure 6, copied below, depicts a TWICE comprising dimerization domains (e.g. see [0090]). The targeting moieties (two sets each of four striped ovals) of the first and second components are shown. Each component comprises an immune cell binding domain (black domains of each component) and a complementary binding domain (white domains of each component). The dimerization domain is attached to the immune cell binding domain and to the complementary binding domain of each component via a linker (such that each component has a dimerization domain A and dimerization domain B that can associate) (e.g. see [0090]). The dimerization domains may be a receptor/ligand pair (e.g. see [00239] and [00247]).
Figure 6 copied from Preyer et al. 2020 (WO2020131697)
Preyer et al. also teach that the linkers between the dimerization domain components and the polypeptide chains may contain a sequence that can be cleaved by a protease and that these sequences may be cleaved by the same or different proteases (e.g. see [00516]). Protease cleavage sites listed in Table 1 or 2 may also be employed which includes SEQ ID NO: 76 which comprises a protease cleavage site for C2a and Bb (e.g. see [00281] and Table 1). Preyer et al. also teach several uPa cleavable linkers in Table 1 (SEQ ID NOs: 77-80) and the GGGGS linker (SEQ ID NO: 85).
Preyer et al. also teach that the targeting moiety may comprise an antibody (e.g. see [0070]). A skilled artisan would recognize that a full length antibody comprises a dimeric Fc region and VH and VL regions.
Preyer et al. also teach a kit comprising a TWICE construct like the one described above comprising a dimerization domain (e.g. see [00326]). It is noted that Preyer et al. do not teach that the kit comprises instructions for use. However, where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. See MPEP 2112.01.III.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 8, 10, 14, 15, 22, 25, 35, 42, 71, 73, 79-81, 86, 89, and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Autio et al. 2020 (Clin Cancer Res. 26(5): 984-989) in view of Lin et al. 2020 (J. Biomed. Sci. 27(76); 1-20, an IDS reference filed 08/07/2023) and Kim and Cochran 2017 (Curr. Opin. Chem. Biol. 38: 62-69).
Autio et al. teach that while immunotherapies prolong survival in patients with various tumor types, they can result in toxicity because the desired systemic immunostimulatory effects on the tumor also occur in healthy tissue (e.g. see page 984, left column, first paragraph). Given the important link between immunotherapy efficacy and toxicity, identifying strategies to uncouple the two is important in cancer drug development (e.g. see page 984, right column, second paragraph). One potential solution is to preferentially activate drugs in tumors and spare healthy tissue through an antibody prodrug or “proantibody” approach. Similar to nonbiologic prodrug medicines that have been proven safe and effective in a variety of therapeutic areas including cancer, antibody prodrugs may enable administration of the antibody at otherwise intolerable doses or in combination with a chemotherapeutic agent that would otherwise have a high toxicity rate, thereby allowing longer durations of therapy than achievable by the parent antibody alone (e.g. see page 984, right column, second paragraph).
Autio et al. teach that a class of recombinant, proteolytically activated antibody prodrugs called Probody therapeutics, which exploit the hallmark dysregulation of protease activity in tumors and are designed to largely restrict drug activity to the tumor microenvironment (TME) (e.g. see page 986, left column, first paragraph under “Probody Therapeutics). A Probody therapeutic consists of three modular components—(1) an active anticancer monoclonal IgG antibody or fragment of a variable region, (2) a masking peptide linked to the N-terminus of the light chain, and (3) a protease-cleavable substrate linker peptide—produced as a single (or fusion) protein using recombinant antibody production methodology. In healthy tissue, the Probody therapy remains largely intact and blocked from target binding and retains the long circulatory half-life expected for mAb therapies. When a Probody therapeutic reaches the TME, tumor-associated proteases cleave the substrate linker, which releases the mask, enabling the antibody to bind target antigen (e.g. see page 986, left column, first paragraph under “Probody Therapeutics).
It is noted that the antibodies of a proantibody technology taught by Autio et al. comprise a dimeric Fc region (e.g. see Figure 1).
Autio et al. also teach that antibodies blocking the inhibitory checkpoints CTL-associated antigen-4 (CTLA-4) and programmed death 1 (PD-1), or its ligand PD-L1, restore T-cell–mediated antitumor immune responses and have emerged as effective immune-based cancer treatments (e.g. see paragraph spanning pages 984 and 985). Although immune checkpoint inhibitors (ICIs) demonstrate anticancer efficacy with variable response rates across tumor types and patient populations, most patients are nonresponsive to monotherapy; thus, combination strategies have been explored (e.g. see paragraph spanning pages 984 and 985). PD-1/PD-L1 inhibitors may have greater antitumor efficacy with fewer immune-related adverse events (irAEs) than CTLA-4 inhibitors (e.g. see page 985, fourth paragraph). Nonetheless, while ICI monotherapy is generally well tolerated compared with traditional chemotherapy, potentially life-threatening irAEs can occur during and up to 1 year after treatment (e.g. see page 985, left column, second paragraph). Thus, new strategies to maintain efficacy and reduce toxicity of ICIs are needed (e.g. see page 985, left column, second paragraph).
Autio et al. also teach that T-cell–engaging bispecific antibodies (TCBs) are potent therapeutics designed to direct the activity of cytotoxic T cells to tumors (e.g. see page 985, right column, third paragraph). TCBs are dual-targeted and can bind to two different targets (i.e., cell-surface receptors) on the same or different cells. Such dual binding potentially enhances therapeutic antitumor efficacy by simultaneously blocking multiple targets involved in pathogenesis, activating cell signaling, inducing antibody-dependent cell-mediated cytotoxicity, avoiding resistance and increasing antiproliferative effects, and temporarily engaging a patient's own cytotoxic T cells to lyse cancer cells. Two approved TCBs for cancer immunotherapy are catumaxomab, which targets CD3 and EpCAM to treat malignant ascites; and blinatumomab, which targets CD19 and CD3 to treat Philadelphia chromosome–positive acute lymphoblastic leukemia. However, these highly potent TCBs target healthy tissue even with low antigen expression, resulting in significant on-target, off-tumor toxicity (e.g., cytokine release autoimmunity) that can limit dosing. Therefore, TCB levels necessary for therapeutic efficacy have been difficult to reach without excessive toxicity and novel methods are necessary to engage the potent antitumor activity of TCBs while limiting off-target toxicity (e.g. see page 985, right column, third paragraph).
In principle, a distinct advantage of Probody technology is its potential application to any therapeutic antibody, including ICIs and TCBs (e.g. see page 986, left column, third paragraph). In vitro studies demonstrated that an unmasked Probody-TCB exhibit potent dose-dependent tumor killing, whereas the masked molecule reduces cytotoxicity by more than 100,000-fold. Thus, Probody-TCB might enable the development of T-cell–engaging bispecific therapeutics against broadly expressed targets such as EGFR (e.g. see page 986, left column, third paragraph).
Autio et al. do not teach that the mask of the proantibody is a receptor-ligand pair; or wherein the receptor-ligand pair is capable of binding to an immunomodulatory target, such as PD-1-PD-L1.
Lin et al. teach antibody locks (or masks) as an antigen-binding fragment for shielding antigen binding ability of specific Ab drugs (e.g. see the Figure caption for Figure 5). See Figure 5 copied below. Figure 5A depicts a trivalent bi-specific Ab design wherein a disulfide-stabilized variable fragment (dsFv), which is specific against c-Met antigen that is deregulated in several types of cancer, is linked to the C-terminus of the heavy chain of a bivalent anti-HER3 Ab with one-armed protease substrate peptide (GPLGMLSQ, GPLGLWAQ and GPLGIAGQ for MMP-2 and MMP-9, and GGGRR for urokinase plasminogen activator (uPA). In this design, the c-Met binding ability of dsFv is sterically interfered with by the Fc portion of the front anti-HER3 Ab. However, after proteolytic processing by the corresponding protease, the dsFv is swiveled open and recovers its c-Met binding activity.
Figure 5B depicts an alternative construct known as an activatable dual variable domain (aDVD) Ab. In the aDVD, the dsFv from an Ab against intercellular adhesion molecule 1 (ICAM-1) is fused to the N-terminus of light and heavy chain of anti-TNF-α Ab (Infliximab and Adalimumab) with MMP-1-cleavable sequence (e.g. see paragraph spanning pages 7 and 8). In this strategy, the outer arm of the anti-ICAM-1 variable domain retains its antigen binding ability and significantly masks the TNF-α binding ability of Infliximab or Adalimumab in the inner arm by greater than 1000-fold in KD as measured by surface plasmon resonance (SPR) in vitro. However, in the presence of the MMP-1 enzyme the mask is sufficiently cleaved and restores the TNF-α binding ability of aDVD and locally accumulates aDVD in the disease region (e.g. see paragraph spanning pages 7 and 8).
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Figure 5 of Lin et al. 2020 (J. Biomed. Sci. 27(76); 1-20, an IDS reference filed 08/07/2023)
Kim and Cochran teach that while there is a primary focus on the development of antibody therapeutics for cancer treatment, there are significant benefits to developing ligands or receptors themselves as drug candidates (e.g. see paragraph spanning pages 65 and 66). In particular, many ligand/receptor interactions have affinities in the low nM to pM range. Monoclonal antibodies typically bind their targets with affinities in the low nM range, and thus often will not effectively inhibit such high affinity ligand/receptor interactions (e.g. see paragraph spanning pages 65 and 66). In addition to more easily achieving ultra-high affinity binding necessary to inhibit a strong ligand/receptor interaction, using a native ligand or receptor as a therapeutic candidate likely ensures that a biologically-relevant epitope is targeted (e.g. see paragraph spanning pages 66 and 67).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Autio et al. to incorporate the teachings of Lin et al. and Kim and Cochran to include that the mask of the proantibody is a receptor-ligand pair and wherein the receptor-ligand pair is capable of binding to an immunomodulatory target, such as PD-1-PD-L1.
Given that masks (or locks) of a proantibody can be antigen-binding fragments which can be fused to and antibody by one protease cleavable linker and one uncleavable linker in order permit, upon proteolytic cleavage, retention of the antigen-binding fragment on the antibody through the uncleavable linker thereby permitting binding of an additional target by the antigen-binding fragment which is not a target that binds the Fab of the underlying antibody (Lin et al.); and the significant benefits to developing ligands or receptors themselves as drug candidates instead of antibodies (Kim and Cochran); it would have been obvious to a skilled artisan, with the goal of designing an activatable trifunctional bispecific T-cell engaging antibody, to experiment with substituting the mask is Autio et al.’s proantibody with a receptor-ligand pair that is fused to the antibody by one protease cleavable linker and one uncleavable linker with a reasonable expectation of success.
In this design, the receptor-ligand pair, which is attached to the N-terminus of a light and heavy chain of an antibody by one protease cleavable linker and one uncleavable linker, would permit (1) masking of the antigen-binding domains of the underlying antibody by steric hindrance in the uncleaved state and (2) upon proteolytic cleavage, shedding of one component of the receptor-ligand pair and retention of the other on the antibody through the uncleavable linker thereby permitting binding of an additional target by the retained receptor or ligand that is not a target that binds the Fab of the underlying antibody.
Furthermore, given the success of targeting the immune checkpoint proteins PD-1/PD-L1 in order to restore T-cell–mediated antitumor immune responses in anticancer immunotherapies (Autio et al. and Kim and Cochran); it would have been obvious to a skilled artisan to select PD-1 and PD-L1 as the receptor-ligand pair for the activatable trifunctional bispecific T-cell engaging antibody taught by Autio et al. in view of Lin et al. and Kim and Cochran with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Autio et al. 2020 (Clin Cancer Res. 26(5): 984-989) in view of Lin et al. 2020 (J. Biomed. Sci. 27(76); 1-20, an IDS reference filed 08/07/2023) and Kim and Cochran 2017 (Curr. Opin. Chem. Biol. 38: 62-69), as applied to claim 1, and further in view of Klein et al. 2014 (Protein Eng. Des. Sel., 27(10), 325-330).
The combined teachings of Autio et al. in view of Lin et al. and Kim and Cochran pertaining to claim 1 and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching the linker is a (Gly4Ser)n, polyproline, and/or an (EAAAK)n linker.
Klein et al. teach that linkers can be classified into three groups: flexible, rigid and cleavable (e.g. see page 325, right column, third paragraph). Flexible linkers are generally composed of small, non-polar or polar residues such as Gly, Ser and Thr. The most common is the (Gly4Ser)n linker (Gly–Gly–Gly–Gly–Ser)n, where n indicates the number of repeats of the motif. Polyglycine linkers have also been evaluated, but the addition of a polar residue such as serine can reduce linker–protein interactions and preserve protein function. More rigid linkers including polyproline motifs and an all α-helical linker A(EAAAK)nA have also been developed (e.g. see page 325, right column, third paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Autio et al. in view of Lin et al. and Kim and Cochran as applied to claim 1 and to incorporate the teachings of Klein et al. to include that the linker is a (Gly4Ser)n, polyproline, and/or an (EAAAK)n linker.
Given that (Gly4Ser)n, polyproline, and (EAAAK)n linkers are very commonly used in fusion proteins; it would have been obvious to a skilled artisan to experiment with incorporating one or more of these sequences into the peptidic linkers of the activatable trifunctional bispecific T-cell engaging antibody taught by Autio et al. in view of Lin et al. and Kim and Cochran with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 35, 79, 81, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Autio et al. 2020 (Clin Cancer Res. 26(5): 984-989) in view of Lin et al. 2020 (J. Biomed. Sci. 27(76); 1-20, an IDS reference filed 08/07/2023) and Kim and Cochran 2017 (Curr. Opin. Chem. Biol. 38: 62-69), as applied to claims 1, 35, 79, and 81, and further in view of Bacac et al. 2017 (US20170174786A1).
The combined teachings of Autio et al. in view of Lin et al. and Kim and Cochran pertaining to claims 1, 35, 79, and 81 and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching the anti-CD3 CDRs as recited in claim 84.
Bacac et al. teach a T cell activating bispecific antigen binding molecule which specifically binds CD3 and CD19; wherein the antigen binding moiety which specifically binds to CD3 comprises the heavy chain complementarity determining region (CDR) 1 of SEQ ID NO: 4, the heavy chain CDR 2 of SEQ ID NO: 5, the heavy chain CDR 3 of SEQ ID NO: 6, the light chain CDR 1 of SEQ ID NO: 8, the light chain CDR 2 of SEQ ID NO: 9 and the light chain CDR 3 of SEQ ID NO: 10 (e.g. see claim 7). It is noted that the anti-CD3 CDRs taught by Bacac et al. are identical to the CDRs of item “(c)” recited in instant claim 84. See sequence alignment below.
Query Match 25.5%; Score 170; DB 1; Length 38;
Best Local Similarity 45.2%;
Matches 38; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 31 TYAMNWVRQAPGKGLEWVSRIRSKYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRA 90
||||| |||||||||||||||||||
Db 1 TYAMN--------------RIRSKYNNYATYYADSVKG---------------------- 24
Qy 91 EDTAVYYCVRHGNFGNSYVSWFAY 114
||||||||||||||
Db 25 ----------HGNFGNSYVSWFAY 38
Query Match 20.8%; Score 119.5; DB 1; Length 30;
Best Local Similarity 39.0%;
Matches 30; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 23 GSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGAQP 82
|||||||||||||| |||||||
Db 1 GSSTGAVTTSNYAN---------------GTNKRAP------------------------ 21
Qy 83 EDEAEYYCALWYSNLWV 99
|||||||||
Db 22 --------ALWYSNLWV 30
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Autio et al. in view of Lin et al. and Kim and Cochran as applied to claims 1, 35, 79, and 81 and to incorporate the teachings of Bacac et al. to include that the anti-CD3 CDRs as recited in claim 84.
Given that a T cell activating bispecific antigen binding molecule comprising the anti-CD3 CDRs of item “(c)” recited in instant claim 84 has already been successfully made; it would have been obvious to a skilled artisan to experiment with selecting Bacac et al.’s anti-CD3 antibody for the anti-CD3 arm of the activatable trifunctional bispecific T-cell engaging antibody taught by Autio et al. in view of Lin et al. and Kim and Cochran with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 8, 10, 14, 15, 22, 25, 35, 42, 71, 73, 79-81, 84, 86, 89, and 97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7-11, 13-18, 20, 21, 23-26, 28-37, 39-49, 54, 55, and 59 of Co-pending U.S. Application No. 18/783,028 (the ‘028 Application) in view of Autio et al. 2020 (Clin Cancer Res. 26(5): 984-989).
The instant claims are drawn to a fusion protein comprising: a biologically functional protein, a ligand-receptor pair, a first peptidic linker and a second peptidic linker; wherein the biologically functional protein comprises at least a first polypeptide and a second polypeptide; and the ligand-receptor pair comprises an extracellular portion of an immunoglobulin superfamily receptor and its cognate ligand or a receptor-binding fragment thereof; wherein the ligand is fused to a terminus of the first polypeptide via the first peptidic linker; the receptor is fused to the same respective terminus of the second polypeptide via the second peptidic linker; and the first and second peptidic linkers are of sufficient length to allow pairing of the ligand and receptor; and a kit.
The claims in the ‘028 Application are drawn to trispecific fusion proteins comprising:(i) a first binding domain capable of binding CD3 on the surface of a cytotoxic effector cell; (ii) a second binding domain capable of binding a tumor associated antigen(TAA) on the surface of a tumor cell; (iii) a third binding domain capable of binding PD-L1 on the surface of a tumor cell; and (iv) a scaffold, wherein the first binding domain, the second binding domain and the third binding domain are operably linked to the scaffold; a tetravalent and trispecific fusion protein; a pharmaceutical composition; and a method of producing.
The claims in the ‘028 Application differ from the instant invention by not teaching that the PD-1 domain is a part of a receptor-ligand pair with PD-L1 or wherein the PD-L1 is linked to the fusion protein by a protease cleavable linker.
The teachings of Autio et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘028 Application to incorporate the teachings of Autio et al. to include that the PD-1 domain is a part of a receptor-ligand pair with PD-L1 and wherein the PD-L1 is linked to the fusion protein by a protease cleavable linker.
Given that there is a need for new strategies to maintain efficacy and reduce toxicity of ICIs and TCBs and the distinct advantage of applying the Proantibody technology to any therapeutic antibody, including ICIs and TCBs; it would be obvious to a skilled artisan to experiment with modifying the ‘028 Applications’ trispecific fusion proteins to introduce the cognate ligand of PD-1, namely PD-L1, to the fusion protein by a protease cleavable linker in order to make an activatable trifunctional bispecific T-cell engaging antibody with a reasonable expectation of success.
In this design, the PD-1-PD-L1 pair, which is attached to the N-terminus of a light and heavy chain of an antibody by one protease cleavable linker and one uncleavable linker, would permit (1) masking of the binding domains of the underlying TCB and ICI in the uncleaved state and (2) upon cleavage by a protease, unmasking of the TCB for target binding and retention of the PD-1 on the TCB through an uncleavable linker to permit binding of an additional target (i.e. PD-L1) to the TCB in the tumor microenvironment specifically.
Therefore, the claims in the ‘028 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7-11, 13-18, 20, 21, 23-26, 28-37, 39-49, 54, 55, and 59 of Co-pending U.S. Application No. 18/783,028 (the ‘028 Application) in view of Autio et al. 2020 (Clin Cancer Res. 26(5): 984-989), as applied to claim 1, and further in view of Klein et al. 2014 (Protein Eng. Des. Sel., 27(10), 325-330).
The combined teachings of the ‘028 Application in view of Autio et al. pertaining to claim 1 and the rationale for combining them are outlined in the NSDP rejection above.
The combined reference teachings differ from the instant invention by not teaching the linker is a (Gly4Ser)n, polyproline, and/or an (EAAAK)n linker.
The teachings of Klein et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modify the combined teachings of the ‘028 Application in view of Autio et al. as applied to claim 1 and to incorporate the teachings of Klein et al. to include that the linker is a (Gly4Ser)n, polyproline, and/or an (EAAAK)n linker.
Given that (Gly4Ser)n, polyproline, and (EAAAK)n linkers are very commonly used in fusion proteins; it would be obvious to a skilled artisan to experiment with incorporating one or more of these sequences into the peptidic linkers of the activatable trifunctional bispecific T-cell engaging antibody taught by of the ‘028 Application in view of Autio et al. with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the claims in the ‘028 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641