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 .
Status of the Claims
The claims filed 08/09/2024 are acknowledged. No restriction requirement is being imposed in the instant case. Claims 1-21 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e), 365(c) and 120 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 disclosure in provisional application serial no. 62/798,903, PCT/US2020/015659 and application serial no. 17/426,886, thus, the priority date of claims 1-21 is 01/30/2019.
Claim Interpretation
The Y92L clipped species is interpreted as an aflibercept species having the amino acid sequence set forth in instant SEQ ID NO: 3, which lacks the initial 92 amino acids (see specification at paragraph [0036]).
Claim 2 recites a composition comprising a mixture of aflibercept species, wherein the amount of Y92L clipped species in the composition is less than 5.0%, as determined by rCE-SDS and/or at least 30% of the aflibercept species is occupied at position N68, as determined by rCE-SDS. Claim 2 is interpreted as encompassing any of the following embodiments:
The amount of Y92L clipped species in the composition is less than 5.0%;
At least 30% of the aflibercept species is occupied at position N68; or
Both (a) and (b).
Claims 3 and 5 limit the first embodiment (a), claim 4 limits the second embodiment (b) and claim 6 limits the third embodiment (c).
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.
Claim 11 is 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. Claim 11 recites the limitation “wherein the amount of Y92L clipped species” in line 1. There is insufficient antecedent basis for this limitation in the claim, since claim 10, from which claim 11 depends, does not refer to the Y92L clipped species.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is not supported by either a specific or substantial asserted utility or a well-established utility. Claim 1 is drawn to Y92L a clipped species of aflibercept comprising SEQ ID NO: 3. The specification discloses that the Y92L clipped species results from degradation of the protein in culture. For instance, Figure 2 shows the reduced binding of the Y92L clipped species to VEGF-A. The specification discloses methods for reducing the formation of the Y92L clipped species (see for example p. 20, Table 2 and Example 2, pages 21-22). The art teaches that clipping is major concern for therapeutic Fc-fusion proteins contributing to their degradation in culture and storage. See Chakrabarti et al. (Int. J. Mol. Sci. 2016, 17, 913; doi:10.3390/ijms17060913—on IDS filed 08/09/2024), who describe “clipping” as a source of protein degradation (see abstract and p. 2, 3rd paragraph
Degradation of recombinant proteins in culture is a common and serious problem. Degradation of most proteins, including recombinant monoclonal antibodies and fusion proteins, may be attributed to host cell-derived proteases, which may be very site specific or have a broad substrate range. The most common strategies adopted to control proteolysis are engineering host cell lines by making them protease-negative or mutants for intracellular protease expression and for efficient post-translational modification and secretion. Some other methods used are genetic engineering, by mutating known protease sites in transfecting gene of interest, isolating and analyzing the type of protease secreted by CHO cells and inhibiting specifically, media optimization, lowering culture temperature, use of protease inhibitors and early product harvesting as lysis of non-viable cells in culture releases proteases which accumulate over time and degrade the desired product. (Citations omitted by examiner).
The specification does not make any statements asserting that the Y92L clipped species is useful for any particular purpose. Given that the specification describes the Y92L clipped species in terms of a purification method for reducing or eliminating the Y92L species (see paragraph [0084], for example), and the knowledge in the art that clipping is a source of Fc-protein degradation, a person of ordinary skill would not immediately recognize a specific and substantial utility for the claimed invention. In other words, why would a clipped species known to be a protein degradation by-product and based on the characteristics of reduced binding disclosed in the instant specification be useful? The instant application fails to identify a specific and substantial utility for what is essentially a protein degradation by-product that one should take care to reduce in culture. To comply, applicant must reply by indicating why the invention is believed useful and where support for any subsequently asserted utility can be found in the specification as filed.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
As noted above, claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is not supported by either a specific or substantial utility or a well-established utility. (See the rejection above under 35 USC 101, hereby incorporated). As such, claim 1 is also rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. Specifically, because the claimed invention is not supported by either a specific or substantial asserted utility or a well-established utility for the reasons set forth above, one skilled in the art clearly would not know how to use the claimed invention. As noted above in the rejection under 35 USC 101, the instant specification discloses methods for reducing the formation of the Y92L clipped species (see for example p. 20, Table 2 and Example 2, pages 21-22) and the art teaches that clipping is major concern for therapeutic Fc-fusion proteins contributing to their degradation in culture and storage (see Chakrabarti et al., abstract and p. 2, 3rd paragraph).
Due to the large quantity of experimentation necessary to determine how to use a degradation product of aflibercept with reduced VEGF-A binding, the lack of direction/guidance presented in the specification regarding, and the absence of working examples directed to the same, the complex nature of the invention, and the state of the prior art, which teaches that clipped Fc-fusion products are degradation by-products, undue experimentation would be required of the skilled artisan to use the claimed invention.
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 § 102
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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen (US2013/0129830—on IDS filed 08/09/2024). Claim 1 recites a Y92L clipped species of aflibercept comprising SEQ ID NO: 3. Chen discloses a VEGF-Trap protein having the sequence set forth in SEQ ID NO: 1, which is also referred to therein as “Aflibercept” (see paragraphs [0026] and [0043]). The specification defines the Y92L clipped species as comprising SEQ ID NO: 3 at p. 2, line 23. The claim recites “comprising” which is open language, and does not exclude other elements, for example, amino acids, from the claim. The sequence set forth in SEQ ID NO: 1 of Chen shares 100% sequence identity with instant SEQ ID NO: 3. See the sequence alignment in APPENDIX I. Using the broad definition set forth at p. 2, the amino acid sequence disclosed by Chen meets the limitations of the claim.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Papadopoulos et al. (US Patent 7,070,959—on IDS filed 05/18/2026). Claim 1 recites a Y92L clipped species of aflibercept comprising SEQ ID NO: 3. Papadopoulos et al. disclose the amino acid sequence of VEGF-Trap protein or aflibercept, set forth in SEQ ID NO: 16 and how to make the protein recombinantly in Chinese Hamster Ovary (CHO) cells (see columns 13-17; column 29, Example 21; claims 1-15). The claim recites “comprising” which is open language, and does not exclude other elements, for example, amino acids, from the claim. The amino acid sequence of the aflibercept protein disclosed by Papadopoulos (SEQ ID NO: 16) shares 100% sequence identity with instant SEQ ID NO: 3. See the sequence alignment in APPENDIX II. Using the broad definition set forth at p. 2, the amino acid sequence disclosed by Chen meets the limitations of the claim.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US2013/0129830) in view of Chakrabarti et al. (Int. J. Mol. Sci. 2016, 17, 913). Both references are cited above. 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. Claim 1 recites a Y92L clipped species of aflibercept comprising SEQ ID NO: 3. Chen discloses a VEGF-Trap protein having the sequence set forth in SEQ ID NO: 1, which is also referred to therein as “Aflibercept” (see paragraphs [0026] and [0043]). The specification defines the Y92L clipped species as being clipped at p. Y92L, which results in an aflibercept species lacking the initial 92 amino acids (see p. 8, lines 32-33; p. 10, lines 12-14). The sequence set forth in SEQ ID NO: 1 of Chen shares 100% sequence identity with instant SEQ ID NO: 3. See the sequence alignment in APPENDIX I.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Chen does not teach that the protein is clipped or that it is clipped at Y92L. Chakrabarti et al. teach that therapeutic Fc-fusion proteins produced in “host cells by recombinant DNA technology are often fully or partially degraded in culture” (see p. 2, 2nd paragraph). Chakrabarti performed an experiment in which an VEGFR1(D1-D3)-Fc protein was produced recombinantly and the protein was clipped “immediately after expression in the host cell lines” and that the clipping was “probably independent of [the] host cell” (see paragraph bridging pages 3 and 4). Chakrabarti et al. also describe methods of decreasing clipping, including lowering the temperature of the culture and adding protease inhibitors, which resulted in “the majority of the protein present in the intact form” (see pages 7-8).
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that upon reading Chakrabarti and colleagues, that Fc-fusion proteins such as aflibercept are clipped during the recombinant expression process. While Chakrabarti et al. exemplify a different Fc-fusion protein and do not specifically teach the Y92L clipped aflibercept species, this limitation does not impart a patentable distinction. The claim recites a limitation describing how the aflibercept functions when subjected to proteases during recombinant production, which amounts to an explanation of what occurs during the manufacturing process. However, a scientific explanation for the prior art’s functioning does not render an old composition patentably new to the discoverer (see MPEP 2112). Further, the person of ordinary skill in the art would have been motivated to reduce the amount of clipping because Chakrabarti et al. teach that this type of degradation is a common and known problem in recombinant protein production (see abstract and p. 2, 3rd paragraph):
Degradation of recombinant proteins in culture is a common and serious problem. Degradation of most proteins, including recombinant monoclonal antibodies and fusion proteins, may be attributed to host cell-derived proteases, which may be very site specific or have a broad substrate range. The most common strategies adopted to control proteolysis are engineering host cell lines by making them protease-negative or mutants for intracellular protease expression and for efficient post-translational modification and secretion. Some other methods used are genetic engineering, by mutating known protease sites in transfecting gene of interest, isolating and analyzing the type of protease secreted by CHO cells and inhibiting specifically, media optimization, lowering culture temperature, use of protease inhibitors and early product harvesting as lysis of non-viable cells in culture releases proteases which accumulate over time and degrade the desired product. (Citations omitted by examiner).
Furthermore, the person of ordinary skill in the art could have reasonably expected success because clipping is something that routinely occurs during the process of manufacturing recombinant proteins.
Thus, the claim does not contribute anything non-obvious over the prior art.
Claims 1-6 and 10-17 are rejected under 35 U.S.C. 103 as being unpatentable over Papadopoulos et al. (cited above) in view of Karur Ramakrishnan (WO2017/168296—on IDS filed 08/09/2024) and Zhang et al. (Journal of Pharmaceutical and Biomedical Analysis 53 (2010) 1236-1243). Claim 1 recites a Y92L clipped species of aflibercept comprising SEQ ID NO: 3. Claim 2 recites a composition comprising a mixture of aflibercept species, wherein the amount of Y92L clipped species in the composition is less than 5.0%, as determined by rCE-SDS and/or at least 30% of the aflibercept species is occupied at position N68, as determined by rCE-SDS. Claims 3-6 depend from claim 2 and recite the following limitations:
Claim
Y92L clipped species
% of species occupied at N68
(i.e., N-glycosylated)
3
< 0.8% or ≈0.4%
4
≥50%, 50-60%, 39%, 53%, 54%, or 55%
5
1-3%, < 0.8 or ≈0.4%
6
1.1% or 0.4%
54-55%
Claim 10 recites a composition comprising a mixture of aflibercept species that may have any one of the attributes set forth in (a)-(h) of I, any one of the attributes set forth in (a)-(i) of II or any one of the attributes set forth in (a)-(j) of III. Thus, claim 10 reads upon a compound comprising an aflibercept species comprising between 20-75% N-glycosylation at N68. Finally, claim 11 depends from claim 10 and recites that the amount of Y92L clipped species is about 0.4%.
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. Papadopoulos et al. (US Patent 7,070,959) disclose the amino acid sequence of VEGF-Trap protein or aflibercept, set forth in SEQ ID NO: 16 and how to make the protein recombinantly in Chinese Hamster Ovary (CHO) cells (see columns 13-17; column 29, Example 21; claims 1-15). The amino acid sequence of the aflibercept protein disclosed by Papadopoulos shares 100% sequence identity with instant SEQ ID NO: 3. See the sequence alignment in APPENDIX II.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Papadopoulos et al. do not teach that the protein is clipped or that it is clipped at Y92L, nor do they disclose the glycosylation status of residue N68 or the glycosylation and/or galactosylation of other residues. Further, Papadopoulos et al. do not teach how the alternative aflibercept species are measured/determined, e.g., by reduced capillary electrophoresis sodium-dodecyl sulfate (rCE-SDS). Finally, Papadopoulos et al. do not teach the methods of reducing the amount of Y92L clipped species or inappropriate glycosylation of N68 comprising the steps set forth in claims 12-16. Papadopoulos et al. do, however, teach the same protein, aflibercept, made using the same recombinant methods in CHO cells (see instant claim 35), thereby meeting the limitation of instant claim 17.
Karur Ramakrishnan (WO2017/168296) teaches that the process of recombinant protein production by necessity results in some clipped and improperly glycosylated proteins (see p. 2, lines 13-15). While Karur Ramakrishnan exemplifies a different Fc-fusion protein and does not specifically teach clipping at Y92L or the glycosylation status of residue N68, these limitations do not impart patentable distinctions. Even though the glycosylation and degradation profiles of aflibercept are not disclosed in the prior art, Papadopoulos et al. taught the same Fc-protein made by the same method and Karur Ramakrishnan taught that clipped species and improperly glycosylated proteins were routine by-products of recombinant protein production. The claim provides a limitation about what typically happens to the protein when subjected to proteases during recombinant production in CHO cells, which amounts to an explanation of what occurs during the manufacturing process. However, a scientific explanation for the prior art’s functioning does not render an old composition patentably new to the discoverer (see MPEP 2112).
In addition, although Papadopoulos et al. do not teach methods of determining aflibercept species as recited in claim 2, rCE-SDS was a known method of determining antibody impurities (see Zhang et al., abstract; p. 1237, left column, penultimate paragraph). Moreover, claim 2 is drawn to a composition and not a method, thus, the limitation of “as determined by rCE-SDS” does not impart a structural limitation on the recited composition, but rather merely describes how the recited impurities were measured. Thus, the applied prior art references encompass the compounds recited in claims 1-6, 10 and 11.
Regarding methods of making a protein with the desired attributes (instant claims 12-16), Karur Ramakrishnan teaches a method of reducing clipped and improperly glycosylated Fc-fusion proteins, such as aflibercept, by a purification process comprising the steps of: a) capturing the protein from broth using Protein A resin; b) subjecting the eluate of step (a) to anion exchange chromatography; c) subjecting the eluate of step (b) to hydrophobic interaction chromatography; d) subjecting the eluate of step (c) to cation exchange chromatography; and e) collecting the eluate to obtain the purified protein with optional steps of diafiltration being carried out between chromatographic steps (see claims 1 and 2; also p. 4, lines 21-27). Karur Ramakrishnan also teach that the cation exchange chromatography step “is an optional step which may or may not be included” (see p. 4, lines 29-30; also claim 3). Thus, the methods disclosed by Karur Ramakrishnan meet the limitations of claims 12-16.
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to carry out the purification methods taught by Karur Ramakrishnan because impurities accumulated during the recombinant protein production process reduces the efficacy of the desired therapeutic Fc-fusion proteins. The person of ordinary skill in the art would have been motivated to use the methods set forth in WO document by Karur Ramakrishnan because it clearly outlines the steps for removing impurities in “all Fc fusion proteins” resulting from clipping and inappropriate differences in glycosylation proportions to improve desired protein yield (p. 2, lines 1-17), thereby resulting in a “purified protein that meets the specifications for use as a biotherapeutic or a biosimilar” (see p. 12, lines 18-19). Furthermore, the person of ordinary skill in the art could have reasonably expected success because the level of skill in the art of protein purification was high at the time of filing.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Papadopoulos et al., Karur Ramakrishnan and Zhang et al. as applied to claims 1-6 and 10-17 above, and further in view of Leiske (WO2016089919—on IDS filed 08/09/2024). 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 Papadopoulos et al., Karur Ramakrishnan and Zhang et al., and how they meet the limitations of claims 1-6 and 10-17 are outlined above in the preceding rejection and are hereby incorporated.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. While the combined teachings of Papadopoulos et al., Karur Ramakrishnan and Zhang et al. teach the broad outlines of cell culture and harvesting (see Example 1 at p. 8 of Karur Ramakrishnan, for example), they do not teach the specifics of the cell culture and harvesting techniques set forth in instant claims 18-20. Leiske teaches the host cells may be cultured in a batch culture, fed-batch culture, perfusion culture, or combinations thereof (see p. 3, lines 16-18). In addition, Leiske teaches that the cells may be harvested by various methods including centrifugation; precipitation and depth filtration. Both Karur Ramakrishnan and Leiske teach further steps of viral inactivation and ultrafiltration/diafiltration (see sentences bridging pages 4-5 and p. 8, lines 20-21 of Karur Ramakrishnan; p. 22, lines 2-4 of Leiske), thereby teaching the limitation of claim 21.
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to carry out the culture, harvest and purification steps outlined by Leiske because these steps are routine and represent optimization within the art (see MPEP 2144.05(II)(A)&(B)). The person of ordinary skill in the art would have been motivated to carry out these steps because they represent known methods for improving upon recombinant protein production and minimizing impurities. Specifically, recombinant protein production was well established in the prior art. Further, the reference by Leiske provides more guidance and specificity regarding cell culture and harvesting methods. For instance, one having skill in the art would recognize the different methods of cell culture (perfusion, fed-batch) are two known methods capable of producing comparable results and that cells can be harvested by precipitation, centrifugation or depth filtration. Furthermore, the person of ordinary skill in the art could have reasonably expected success because these are all well-established steps in cell culture and protein harvesting protocols.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Papadopoulos et al., Karur Ramakrishnan, Zhang et al. and Leiske as applied to claims 1-6 and 10-21 above, and further in view of Assadourian et al. (WO2014/020160—on IDS filed 08/09/2024). Claim 7 is drawn to a composition comprising a mixture of aflibercept species, wherein the total sialic acid content of aflibercept species is between 6.0 and 10.0 mol/mol protein, as determined by LC-MS based peptide mapping method and/or the aflibercept species comprise between 1.0-12% afucosylation in the Fc domain. Claims 8 and 9 depend from claim 7 and recite the following limitations:
Claim
Total Sialic Acid Content
% of Afucosylation
8
6.8, 8.5 or 9.5 (mol/mol protein)
9
< 10%, ≈6%, < 5% or ≈4%
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 Papadopoulos et al., Karur Ramakrishnan, Zhang et al., and Leiske and how they meet the limitations of claims 1-7 and 10-21 are outlined above in the 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 Papadopoulos et al., Karur Ramakrishnan, Zhang et al., and Leiske do not teach the total sialic acid content of claims of the aflibercept species. Assadourian et al. teach aflibercept containing between 8-12 moles of sialic acid/moles of polypeptide (mol/mol protein—see p. 6, lines 20-21; claim 10), which encompasses and overlaps with the range recited in claims 7 and the amount contents recited in claim 8. The MPEP instructs that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists” (see MPEP 2144.05(I)). Further, regarding the percentage of afucosylation, Leiske teaches that there is motivation in the art to increase afucosylation because it enhances antibody dependent cell mediated cytotoxicity (ADCC). Finally, regarding the “as determined by LC-MS based peptide mapping method” limitation in claim 7, the claim is drawn to a composition and not a method, thus, the “as determined by…” limitation does not impart a structural limitation on the recited composition, but rather merely describes how the recited attributes were measured.
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to optimize aflibercept to contain between 8-12 mol/mol protein because sialic acid content between 8-12 mol/mol is consistent with the optimum sialic acid content (see claim 10 of Assadourian and colleagues). Further, it would have been obvious to one having ordinary skill in the art to manipulate afucosylation because this enhances ADCC and therefore the anti-cancer properties of aflibercept. The person of ordinary skill in the art would have been motivated to manipulate these properties because the prior art makes clear they are tied to the efficacy of the drug. See Leiske et al. (see p. 33, lines 20-23):
Glycosylation can affect therapeutic efficacy of recombinant protein drugs. It is well known that variations in Fc glycosylation can affect Fc-mediated effector functions. Afucosylation and high mannose glycans can enhance antibody-dependent cellular cytotoxicity (ADCC) activity.
See also p. 7, lines 7-14:
The type and extent of N-linked glycosylation on IgG1 antibodies are known to affect Fc-mediated effector functions. For example, the level of afucosylation strongly enhances antibody dependent cell mediated cytotoxicity (ADCC) by increasing binding affinity to Fcγ receptors, whereas the level of galactosylation can influence complement dependent cytotoxicity (CDC) activity.
Furthermore, the person of ordinary skill in the art could have reasonably expected success because Assadourian et al. indicate that aflibercept or a biosimilar should contain 8-12 mol/mol protein and Leiske teaches how to manipulate fucosylation.
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claim is allowed.
The art made of record and not relied upon is considered pertinent to Applicant's disclosure. The post-filing date art of Duivelshof et al. (J Sep Sci. 2021; 44: 35-62—on IDS filed 08/09/2024) teaches that therapeutic Fc-fusion proteins have diverse glycosylation profiles and other post-translational modifications that have yet to be fully characterized. Duivelshof et al. also teach:
The modifications that proteins can undergo are considered as degradation products and can be classified either as product-related substances or as impurities. When the degradation product has properties not comparable to those of the desired product, it will be considered as an impurity that may eventually affect the activity, efficacy and safety of the product. Many external factors can contribute to the formation of degradation products, e.g. pH, temperature, light, exposition to surface, storage time, salt concentration, protein concentration, formulation excipients or shaking, as well as intrinsic factors, such as free thiols in the Fc-fusion protein moieties. Due to these potential modifications, the determination of the biopharmaceutical drug purity is difficult to achieve. (Citations omitted by examiner).
In addition, Lee et al. (Int. J. Mol. Sci. 2022, 23, 11807—on IDS filed 08/09/2024) indicate that companies developing Fc-fusion proteins and antibodies keep glycosylation profiles proprietary (p. 2, 2nd paragraph):
The importance of the process and quality controls becomes more obvious for the development of biosimilars. In most cases, the developers of innovative therapeutics will keep their manufacturing process information as proprietary. Therefore, biosimilars developers will have to develop their own process with likely variations from that of the original developers, while maintaining similarity with the reference products with minimum variations in the critical quality attributes.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 5712720911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
APPENDIX I
RESULT 3
US-13-680-069-1
(NOTE: this sequence has 3 duplicates in the database searched)
Sequence 1, US/13680069
Publication No. US20130129830A1
GENERAL INFORMATION
APPLICANT: Regeneron Pharmaceuticals, Inc.
TITLE OF INVENTION: Polymer Protein Microparticles
FILE REFERENCE: 1110A
CURRENT APPLICATION NUMBER: US/13/680,069
CURRENT FILING DATE: 2012-11-18
PRIOR APPLICATION NUMBER: US 61/561,525
PRIOR FILING DATE: 2011-11-18
NUMBER OF SEQ ID NOS: 1
SEQ ID NO 1
LENGTH: 415
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic
Query Match 100.0%; Score 1810; Length 415;
Best Local Similarity 100.0%;
Matches 339; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 LTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 77 LTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVN 136
Qy 61 RDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 137 RDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCP 196
Qy 121 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 197 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 256
Qy 181 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 257 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 316
Qy 241 VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 317 VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 376
Qy 301 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 339
|||||||||||||||||||||||||||||||||||||||
Db 377 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 415
APPENDIX II
Sequence 16, US/10009852
Patent No. 7070959
GENERAL INFORMATION
APPLICANT: Nicholas J. Papadopoulos et al.
TITLE OF INVENTION: MODIFIED CHIMERIC POLYPEPTIDES WITH IMPROVED
TITLE OF INVENTION: PHARMACOKINETIC PROPERTIES AND METHODS OF MAKING
TITLE OF INVENTION: AND USING THEREOF
FILE REFERENCE: REG 710-A-US
CURRENT APPLICATION NUMBER: US/10/009,852
CURRENT FILING DATE: 2001-12-06
PRIOR APPLICATION NUMBER: PCT/US00/14142
PRIOR FILING DATE: 2000-05-23
PRIOR APPLICATION NUMBER: 60/138,133
PRIOR FILING DATE: 1999-06-08
NUMBER OF SEQ ID NOS: 38
SEQ ID NO 16
LENGTH: 458
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 100.0%; Score 1810; Length 458;
Best Local Similarity 100.0%;
Matches 339; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 LTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 119 LTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVN 178
Qy 61 RDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 179 RDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCP 238
Qy 121 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 239 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 298
Qy 181 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 299 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 358
Qy 241 VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 359 VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 418
Qy 301 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 339
|||||||||||||||||||||||||||||||||||||||
Db 419 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 457
Prosecution Insights