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 .
Response to Amendment
The preliminary amendment filed 07/17/2024 is acknowledged. Claims 3-13, 15-17 and 22 are amended and claims 19-21 and 23-25 are canceled. No restriction is being imposed in this case. Claims 1-18 and 22 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) and 365(c) is acknowledged. Based on the information given by Applicant and an inspection of the prior applications, the examiner has concluded that the subject matter defined in the instant claims is supported by the disclosures in PCT/EP2022/059902 and provisional application serial no. 63/174,855. The priority date of claims 1-18 and 22 of the instant application is deemed to be 04/14/2021.
Claim Objections
Claim 22 is objected to because of the following informalities. Claim 22 recites a method of purifying an EV that “comprises or consists of the polypeptide of claim 1”, which is redundant. Since the claim recites “comprises”, which requires the polypeptide of claim 1 with possible unrecited elements, it also encompasses a polypeptide that has no unrecited elements (consists of).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 1-18 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
(i) Claim 1 recites the modified Fc domain is capable of specifically binding to the Fc binding site of an FcRn. The use of the definite article, “the” in the phrase “the Fc binding site of an FcRn” implies there is a single Fc binding site. The Fc binding site is defined in the instant specification as referring “the region of an FcRn polypeptide that binds to Fc domain of an immunoglobulin”. According to Vaughn et al. (J. Mol. Biol. 1997 274, 597-607., see p. 598, Figure 1 description):
The high affinity binding site for IgG is formed by a homodimer of two FcRn molecules identified as the “primary FcRn”…and the “secondary FcRn”…Each FcRn molecule is composed of a multidomain heavy chain…and a single domain light chain (β2m). The Fc ligand…interacts with the heavy chain α2 domain and β2m domain of the primary FcRn, and the heavy chain α3 domain of the secondary receptor.
The prior art suggests that the Fc binding site of an FcRn involves the α2, β2m and α3 domain of two FcRn molecules, therefore, it is not clear to which “Fc binding site of an FcRn the claim is referring to. Further complicating this is Vaughn et al. also teach that “there is a distinction between the ‘functional epitope’ (those residues that exert a major effect upon the binding affinity…) and the ‘structural binding site’ (all residues at the interface)” and that in “the case of the interaction between FcRn and IgG, the structural binding site cannot be identified with certainty” (see p. 602, left column). Finally, dependent claims 4 and 5 recite the modified Fc domain is capable of specifically binding to particular positions on human FcRn, which suggest there is more than a single “Fc binding site of an FcRn. Claims 18 and 22 also recite “the Fc binding site of an FcRn, and therefore also have this issue”.
(ii) The MPEP section 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “[e]xaminers should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim.” Claim 1 defines the claimed polypeptide in terms of its functional capabilities, namely binding to FcRn and not forming homodimers, i.e., monomeric. The functional limitations of claims 2-8 are as follows.
Claim(s)
Functional Limitation(s)
2-3
Polypeptide has Kd at pH 6.5 at most 10-4 M and Kd at pH 7.4 at least 10-4 M
4-5
Modified Fc domain binds epitope between residues 135-158 of FcRn
6
Polypeptide does not substantially bind C1q or FcγRI-III
7-8
Modified Fc domain CDC, ADCC, ADCP and ADIN activity is decreased by 10-50% or 1-5 fold
Claims 2-8 recite that the modified Fc domain and polypeptide has certain functional characteristics, but these functional limitations do not materially limit the structure of the polypeptide recited in claim 1 because functional language does not set forth well-defined structural boundaries. A person having ordinary skill would not know the structure required by the claims or the structure necessary for avoiding infringement. Since the claim fails to meet all (3) criteria set forth in MPEP 2173.05(g), then the claims are rejected as being indefinite.
(iii) Claims 9 and 10 depend from claim 1 and recite “the FcRn binding polypeptide”. There is insufficient antecedent basis for this limitation in the claim since claim 1 merely refers to “a polypeptide”. Even though part (b)(i) of claim 1 recites a modified Fc domain capable of specifically binding to the Fc binding site of an FcRn, it is not sufficiently clear from claim 1 that the polypeptide as a whole unambiguously defines an FcRn binding polypeptide. Note this issue could be addressed by amending claim 1, line 1 to recite “An FcRn binding polypeptide”.
(iv) Claim 12 contains the trademark/trade names Nanobody®, Avibodytm, DARPin®, BiTE®, PROBODY®, Centyrintm, Affibody®, Affilin®, Anticalin®, Adnectintm, Tribodytm and Nanofitin®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the targeting domains and, accordingly, the identification/description is indefinite.
(v) Claim 12 also recites exemplary language, namely, the phrase “e.g.”, which means “for example” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Similarly, the parenthetical recitation of BiTE® in claim 12 is presented as an example of a T-cell engager, and is therefore also indefinite.
Claims 2-17 and 22 are also included in this rejection for depending upon indefinite claims without resolving the indefiniteness.
Notice for all US Patent Applications filed on or after March 16, 2013: 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.
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 1-3 and 6-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (WO2018/015535—on IDS filed 10/13/2013) in view of Wang et al. (Front. Immunol. 8:1545. doi: 10.3389/fimmu.2017.01545). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Wiklander et al. teach a non-covalent complex between (i) a fusion protein, and (ii) an Fc-containing protein, i.e., Fc domains, characterized in that the fusion protein comprises at least one Fc binding polypeptide fused to at least one exosomal polypeptide, which may be a transmembrane polypeptide, wherein the Fc binding polypeptide binds to the Fc containing protein and the fusion proteins may comprise linkers and transmembrane domains (see claims 1-12; p. 3, 2nd paragraph; top of p. 23; paragraph bridging pages 27-28). For example, an exosomal polypeptide may be CD9 (see claim 4 of Wiklander and colleagues), which is a multi-pass transmembrane protein. A schematic of the complex is depicted in Figure 1 of Wiklander and colleagues:
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Regarding claims 9 and 10, Wiklander et al. teach that the fusion polypeptide can be construed in either the C- or N-terminal direction comprising the exosomal polypeptide (which may be a transmembrane domain) and Fc domain (see p. 27). In addition, Wiklander et al. teach that the fusion polypeptides may comprise linkers (see p. 29). Wiklander et al. also teach using extracellular vesicles as delivery vehicles for the polypeptides, and may have a targeting antibody, such as scFv (see paragraph bridging pages 37-38; claim 9). Further, Wiklander et al. teach a polynucleotide construct encoding for the Fc binding and exosomal polypeptide, a vector comprising and a cell comprising said polynucleotide construct (see claims 18-19, pages 48-49 (under “Materials and methods”).
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Wiklander et al. do not explicitly teach that the Fc domain is capable of binding to the Fc binding site of an FcRn or that the Fc domain is modified so as not to form homodimers. Wang et al. teach mutations to the Fc domain that result in monomeric Fc that binds human FcRn with a Kd of about 0.35-0.54 μM or about 3.5 x 10-7 to 5.4 10-7 M and reduced binding at pH 7.4 (see p. 6, left column and Figure 4). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Wiklander et al. by modifying the Fc domain to be monomeric because the modified Fc fusion proteins taught by Wang et al. “improved transport across FcRn-expressing cells and did not induce Fc-mediated cytotoxicity in vitro (ADCC and CDC—see p. 7, left column, 2nd paragraph)”. Claims 7 and 8 recite that the modified Fc domain has decreased CDC, ADCC, ADCP and/or ADIN activity by 10-50% or 1-5-fold, respectively, which are functional limitations. Since Wang et al. teach that Fc-mediated ADCC and CDC was reduced, it flows therefrom that the prior art product reduces this activity by 10-50% or 1-5-fold. Further, since ADCC and CDC was reduced, it flows therefrom that binding to the C1q and Fcγ receptors was reduced.
The person of ordinary skill in the art would have been motivated to make the modifications to the Fc domain because reducing Fc-cytotoxicity has potential for delivering therapeutic proteins. Furthermore, the person of ordinary skill in the art could have reasonably expected success because Wang et al. teach their “study suggests that the new monomeric IgG1 Fc [molecule] could be potentially applicable in the engineering and development of novel biopharmaceuticals due to its high stability, pH-dependent FcRn binding, and significantly decreased non-specificity compared with the previous[ly] reported monomeric Fc mutants” (see p. 7, right column, last paragraph).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1 and 9-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (WO2018/015535—on IDS filed 10/13/2013) in view of Kannan et al. (US 2012/0244578). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Wiklander et al. teach a non-covalent complex between (i) a fusion protein, and (ii) an Fc-containing protein, i.e., Fc domains, characterized in that the fusion protein comprises at least one Fc binding polypeptide fused to at least one exosomal polypeptide, which may be a transmembrane polypeptide, wherein the Fc binding polypeptide binds to the Fc containing protein and the fusion proteins may comprise linkers and transmembrane domains (see claim 12; top of p. 23; paragraph bridging pages 27-28). For example, an exosomal polypeptide may be CD9 (see claim 4 of Wiklander and colleagues), which is a multi-pass transmembrane protein. A schematic of the complex is depicted in Figure 1 of Wiklander and colleagues:
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Regarding claims 9 and 10, Wiklander et al. teach that the fusion polypeptide can be construed in either the C- or N-terminal direction comprising the exosomal polypeptide (which may be a transmembrane domain) and Fc domain (see p. 27). In addition, Wiklander teaches that the fusion polypeptides may comprise linkers (see p. 29). Wiklander et al. also teach using extracellular vesicles as delivery vehicles for the polypeptides, and may also have a targeting antibody, such as scFv (see paragraph bridging pages 37-38; claim 9). Further, Wiklander et al. teach a polynucleotide construct encoding for the Fc binding and exosomal polypeptide, a vector comprising and a cell comprising said polynucleotide construct (see claims 18-19, pages 48-49 (under “Materials and methods”).
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Wiklander et al. do not explicitly teach that the Fc domain is capable of binding to the Fc binding site of an FcRn or that the Fc domain is modified so as not to form homodimers. Kannan et al. teach modifying the Fc domain (CH2 and CH3) so that it does not form homodimers (see claims 1-26). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Wiklander et al. by modifying the Fc domain to be monomeric because the modified Fc “retains its ability to interact with the FcRn receptor, even without dimerization or the Fab domains, leading to longer serum half-life for proteins/domains that are fused to the monomeric Fc” (see paragraph [0010] of Kannan and colleagues). The person of ordinary skill in the art would have been motivated to make the modifications because the Fc monomer molecules can “extend the half-life of therapeutic proteins” (see paragraph [0087] of Kannan and colleagues). Furthermore, the person of ordinary skill in the art could have reasonably expected success because of the advantages taught by Kannan et al. (see paragraph [0082]):
An [antibody’s] ability to interact with neonatal Fc receptor (FcRn) in a pH dependent manner confers it with extended serum half-life. In preferred embodiments, monomeric Fc molecules of the present invention retain the ability to bind FcRn similarly if not superiorly to wild-type Fc polypeptides (FIG. 6). As shown in Example 2, the monomeric Fc molecules of the present invention can retain the extended serum half-life exhibited by antibodies and, thus, are useful for extending the serum half-life of the polypeptides covalently bound to, e.g. fused to, the monomeric Fc polypeptide.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. and Wang et al. as applied to claims 1-3 and 6-17 above, and further in view of Burmeister et al. (Nature 372, 379-383 (1994) https://doi.org/10.1038/ 372379a0). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Wiklander et al. and Wang et al. and how they meet the limitations of claims 1-3 and 6-17 are outlined above in a preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Wiklander et al. and Wang et al. do not teach the epitope on FcRn to which the modified Fc domain binds as recited in claims 4-5.
Burmeister et al. teach the residues on FcRn that contact Fc, and they include LNGEEF of the human α2 domain (see Table 2(b) at p. 383, which also show the residues in the rat and murine α2 domains of FcRn). Epitopes generally range in size from 5-15 amino acid residues, thus, the binding of Fc to LNGEEF on FcRn is interpreted as encompassing the epitopes recited in instant claims 4-5. It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that the modified Fc domain would bind an amino acid sequence between residues 135-158 of human FcRn, which include LNGEEF, because Burmeister demonstrate that these residues are part of the natural binding sites for Fc. The person of ordinary skill in the art would have been expected that the modified Fc would bind the same portions of FcRn as natural Fc in order to be effective. Furthermore, the person of ordinary skill in the art could have reasonably expected success because Wang et al. taught that their “monomeric Fcs bound FcRn comparably with the wild-type dimeric Fc, providing direct evidence that Fc dimerization is not required for effective binding to FcRn” (see p. 7, left column), thereby suggesting modified monomeric Fc binding binds comparably to native FcRn.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 1-3, 6-17 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. and Wang et al. as applied to claims 1-3 and 6-17 above, and further in view of Wiklander et al. (WO2019/081474—on IDS filed 10/13/2013—hereafter “Wikander II” to avoid confusion). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Wiklander et al. and Wang et al. and how they meet the limitations of claims 1-3 and 6-17 are outlined above in a preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Wiklander et al. and Wang et al. do not teach the method of purifying an EV as recited in claim 22.
Wiklander II teaches purification of engineered extracellular vehicles comprising (i) contacting a medium comprising the EVs with a chromatography matrix comprising Fc domains; (ii) allowing the EVs to adsorb to the Fc domains; and, (iii) eluting the EVs by passing across the chromatography matrix a medium that releases the EVs from the Fc domains, wherein release of the EVs from the Fc domains is triggered by exposure of medium with a suitable pH (see claims 2, 6 and 7). The difference between Wiklander II and instant claim 22 is that Wiklander II discloses the second binding partner represented by the chromatography matrix comprising Fc domains rather than the Fc binding site of an FcRn. Nevertheless, it would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to apply the purification methods taught in Wiklander II because they are based upon the same recognized principle of pH-dependent binding between the Fc domain and FcRn. The person of ordinary skill in the art would have been motivated to apply the pH-dependent binding between the Fc domain and FcRn as a method of purification because traditional exosomal vesicle (EV) purification methods rely on serial centrifugation, which is difficult to scale up, results in contamination, aggregation, low recovery and damage to the EVs (see the paragraph bridging pages 1-2 of Wiklander II). Furthermore, the person of ordinary skill in the art could have reasonably expected success because the methods in Wiklander II are based upon the natural binding of the Fc domain to FcRn at favorable pH, and is therefore gentler than traditional purification methods.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Wiklander II (WO2019/081474 —on IDS filed 10/13/2013). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Wiklander II teaches purification of engineered extracellular vehicles comprising (i) contacting a medium comprising the EVs with a chromatography matrix comprising Fc domains; (ii) allowing the EVs to adsorb to the Fc domains; and, (iii) eluting the EVs by passing across the chromatography matrix a medium that releases the EVs from the Fc domains, wherein release of the EVs from the Fc domains is triggered by exposure of medium with a suitable pH (see claims 2, 6 and 7).
The difference between Wiklander II and instant claim 22 is that Wiklander II discloses the second binding partner represented by the chromatography matrix comprising Fc domains rather than the Fc binding site of an FcRn. Nevertheless, it would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to apply the purification methods taught in Wiklander II because they are based upon the same recognized principle of pH-dependent binding between the Fc domain and FcRn. The person of ordinary skill in the art would have been motivated to apply the pH-dependent binding between the Fc domain and FcRn as a method of purification because traditional exosomal vesicle (EV) purification methods rely on serial centrifugation, which is difficult to scale up, results in contamination, aggregation, low recovery and damage to the EVs (see the paragraph bridging pages 1-2 of Wiklander II). Furthermore, the person of ordinary skill in the art could have reasonably expected success because the methods in Wiklander II are based upon the natural binding of the Fc domain to FcRn at favorable pH, and is therefore gentler than traditional purification methods.
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Wang et al. (Protein Cell 2018, 9(1):63-73) teach how to modify Fc to reduce effector functions (see whole document).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
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