DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-13 are pending in this application and are being examined on the merits.
Applicant’s preliminary amendment to the claims filed 08/05/2024 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Priority
The instant application is a national stage filing under 35 U.S.C. 371 of international application PCT/US2023/012520 filed 02/07/2023, which claims domestic priority to U.S. Provisional Application No. 63/307,456 filed 02/07/2022.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 08/05/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Claim Objections
Claim 8 is objected to for the recitation of the abbreviation “CIMPR” without previously defining the abbreviation. In the interest of improving claim form, Applicant should consider an amendment to recite “cation-independent mannose 6-phosphate receptor (CIMPR)” in the claim before referring to the abbreviation CIMPR thereafter.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-13 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 1 (claims 2-13 dependent therefrom) is indefinite for the recitation of “the total N-linked oligosaccharides”. There is insufficient antecedent basis for this limitation in the claim.
Claims 2 and 3 are indefinite for the recitation of “the N-linked oligosaccharides”. There is insufficient antecedent basis for these limitations in the claims.
Claims 6-7 are indefinite for the recitation of “the acid alpha glucosidase glycans”. There is insufficient antecedent basis for this limitation in the claims.
Claims 9-10 are indefinite for the recitation of the phrase “about 0.1 to 5-fold greater ability to reduce glycogen”. The term “about” is a term of approximation that renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, the limitation of the relative increase in ability for the composition to reduce glycogen is rendered indefinite by the use of the terms.
Claim 12 (claim 13 dependent therefrom) is rejected for the phrase “administering to a subject an effective amount of the composition of claim 1” without reciting the function which is to be achieved by the effective amount because it is unclear from the claim as to whether or not the “subject” is required to have Pompe disease (see MPEP 2173.05(c).III). Applicant may consider an amendment to insert “having Pompe disease” immediately following “subject” in claim 12.
Claim Rejections - 35 USC § 103
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 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 1-5 and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0225953 A1 (cited on the attached Form PTO-892; herein Kornfeld).
Claim 1 (claims 2-5 and 8-11 dependent therefrom) is drawn to a composition comprising acid alpha glucosidase (GAA), wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Claim 12 (claim 13 dependent therefrom) is drawn to a method of treating Pompe disease, the method comprising administering to a subject an effective amount of the composition of claim 1.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylate lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding claim 1, Kornfeld teaches a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld teaches the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally teaches that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of the results and teachings of Kornfeld, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to modify the composition of Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA, which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the composition of Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld teaches cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and teaches highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding claims 2-5, Kornfeld teaches the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not teach that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and teachings of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the composition of Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is presumed to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the composition of Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is presumed to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the composition of Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is presumed to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the composition of Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding claims 12-13, Kornfeld teaches the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld teaches enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally teaches ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the teachings of Kornfeld, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to use the composition of Kornfeld to treat Pompe disease, as taught by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use the composition of Kornfeld to treat Pompe disease, because Kornfeld teaches GAA can be used to treat Pompe disease via ERT.
Therefore, the invention of claims 1-5 and 8-13 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of US 2019/0382742 A1 (cited on the IDS filed 08/05/2024; herein Do).
Claim 6 is drawn to the composition of claim 1, wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Claim 7 is drawn to the composition of claim 1, wherein less than 3% of the GAA glycans comprise hybrid type N-glycans.
The teachings of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. Kornfeld does not teach a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans and/or less than 3% of the GAA glycans comprise hybrid type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding claim 6, Do teaches a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do teaches that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do teaches that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as taught by Kornfeld above. While Kornfeld and Do do not teach a GAA wherein less than 40% of the N-glycans are complex, Do teaches that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as taught by Do, and therefore enzyme uptake by the M6P receptor, as taught by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to modify the composition of Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do teaches rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the teachings of Kornfeld and Do, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do teaches rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld teaches highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding claim 7, Do teaches no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
Therefore, the invention of claims 6-7 would have been obvious to one of ordinary skill in the art before the effective filing date.
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.
A. Claims 1-5 and 8-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 12,492,412 (cited on the attached Form PTO-892; herein patent) in view of Kornfeld.
Regarding instant claim 1, claim 1 of the patent recites a composition comprising a first polynucleotide encoding a lysosomal enzyme, and claim 10 of the patent recites the lysosomal enzyme can be GAA.
The claims of the patent do not recite a GAA wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylated lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding instant claim 1, Kornfeld discloses a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld discloses the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally discloses that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the claims of the patent by replacing the polynucleotide encoding GAA of the patent with the GAA of Kornfeld to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the polynucleotide encoding GAA of the patent and the GAA of Kornfeld both correspond to GAA enzymes, and as such both are capable of being incorporated into compositions as described by the patent and Kornfeld. Thus it would have been obvious to one of ordinary skill in the art to replace the polynucleotide encoding GAA of the patent with the GAA of Kornfeld, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the patent and Kornfeld relate to compositions and GAA.
In view of the results and disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the patent and Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the combined composition of the patent and Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld discloses cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and discloses highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding instant claims 2-5, Kornfeld discloses the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not disclose that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and disclosure of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined composition of the patent and Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding instant claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the patent and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the patent and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the patent and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the patent and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claims 12-13, Kornfeld discloses the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld discloses enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally discloses ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to use the combined composition of the patent and Kornfeld to treat Pompe disease, as disclosed by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use combined composition of the patent and Kornfeld to treat Pompe disease, because Kornfeld discloses GAA can be used to treat Pompe disease via ERT.
Claims 6-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 12,492,412 in view of Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of Do.
The claims of the patent and disclosure of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. The claims of the patent do not recite a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding instant claim 6, Do discloses a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do discloses that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do discloses that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as disclosed by Kornfeld above. While Kornfeld and Do do not disclose a GAA wherein less than 40% of the N-glycans are complex, Do discloses that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as disclosed by Do, and therefore enzyme uptake by the M6P receptor, as disclosed by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the patent and Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do discloses rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the disclosures of Kornfeld and Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the patent, Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of the patent, Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do discloses rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld discloses highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding instant claim 7, Do discloses no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
B. Claims 1-5 and 8-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 37 of copending Application No. 18/835310 (herein reference application) in view of Kornfeld.
Regarding instant claim 1, claim 37 of the reference application recites a composition comprising a lysosomal enzyme selected from a group that includes GAA.
The claims of the reference application do not recite a GAA wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylated lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding instant claim 1, Kornfeld discloses a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld discloses the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally discloses that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the claims of the reference application by replacing the GAA of the reference application with the GAA of Kornfeld to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the GAA of the reference application and the GAA of Kornfeld both correspond to GAA enzymes, and as such both are capable of being incorporated into compositions as described by the reference application and Kornfeld. Thus it would have been obvious to one of ordinary skill in the art to replace the GAA of the reference application with the GAA of Kornfeld, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Kornfeld relate to compositions and GAA.
In view of the results and disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the combined composition of the reference application and Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld discloses cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and discloses highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding instant claims 2-5, Kornfeld discloses the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not disclose that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and disclosure of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding instant claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claims 12-13, Kornfeld discloses the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld discloses enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally discloses ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to use the combined composition of the reference application and Kornfeld to treat Pompe disease, as disclosed by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use the combined composition of the reference application and Kornfeld to treat Pompe disease, because Kornfeld discloses GAA can be used to treat Pompe disease via ERT.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 37 of copending Application No. 18/835310 in view of Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of Do.
The claims of the reference application and disclosure of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. The claims of the reference application do not recite a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding instant claim 6, Do discloses a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do discloses that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do discloses that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as disclosed by Kornfeld above. While Kornfeld and Do do not disclose a GAA wherein less than 40% of the N-glycans are complex, Do discloses that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as disclosed by Do, and therefore enzyme uptake by the M6P receptor, as disclosed by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do discloses rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the disclosures of Kornfeld and Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application, Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of the reference application, Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do discloses rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld discloses highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding instant claim 7, Do discloses no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
C. Claims 1-5 and 8-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 78 of copending Application No. 18/943360 (herein reference application) in view of Kornfeld.
Regarding instant claim 1, claim 78 of the reference application recites a method for treating Pompe disease comprising administering a population of recombinant human GAA. Under the broadest reasonable interpretation, the administration of GAA recited in the claim of the reference application is considered to correspond to a composition comprising GAA.
The claims of the reference application do not recite a composition comprising GAA wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylated lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding instant claim 1, Kornfeld discloses a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld discloses the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally discloses that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the claims of the reference application by replacing the GAA of the reference application with the GAA of Kornfeld to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the GAA of the reference application and the GAA of Kornfeld both correspond to GAA enzymes, and as such both are capable of being incorporated into compositions as described by the reference application and Kornfeld. Thus it would have been obvious to one of ordinary skill in the art to replace the GAA of the reference application with the GAA of Kornfeld, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Kornfeld relate to compositions and GAA.
In view of the results and disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the combined composition of the reference application and Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld discloses cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and discloses highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding instant claims 2-5, Kornfeld discloses the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not disclose that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and disclosure of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding instant claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claims 12-13, Kornfeld discloses the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld discloses enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally discloses ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to use the combined composition of the reference application and Kornfeld to treat Pompe disease, as disclosed by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use the combined composition of the reference application and Kornfeld to treat Pompe disease, because Kornfeld discloses GAA can be used to treat Pompe disease via ERT.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 78 of copending Application No. 18/943360 in view of Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of Do.
The claims of the reference application and disclosure of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. The claims of the reference application do not recite a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding instant claim 6, Do discloses a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do discloses that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do discloses that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as disclosed by Kornfeld above. While Kornfeld and Do do not disclose a GAA wherein less than 40% of the N-glycans are complex, Do discloses that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as disclosed by Do, and therefore enzyme uptake by the M6P receptor, as disclosed by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do discloses rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the disclosures of Kornfeld and Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application, Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of the reference application, Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do discloses rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld discloses highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding instant claim 7, Do discloses no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
D. Claims 1-5 and 8-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/028827 (herein reference application) in view of Kornfeld.
Regarding instant claim 1, claim 1 of the reference application recites a composition comprising rhGAA, which is understood to be recombinant human GAA.
The claims of the reference application do not recite a composition comprising GAA wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylated lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding instant claim 1, Kornfeld discloses a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld discloses the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally discloses that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the claims of the reference application by replacing the GAA of the reference application with the GAA of Kornfeld to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the GAA of the reference application and the GAA of Kornfeld both correspond to GAA enzymes, and as such both are capable of being incorporated into compositions as described by the reference application and Kornfeld. Thus it would have been obvious to one of ordinary skill in the art to replace the GAA of the reference application with the GAA of Kornfeld, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Kornfeld relate to compositions and GAA.
In view of the results and disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the combined composition of the reference application and Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld discloses cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and discloses highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding instant claims 2-5, Kornfeld discloses the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not disclose that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and disclosure of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding instant claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claims 12-13, Kornfeld discloses the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld discloses enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally discloses ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to use the combined composition of the reference application and Kornfeld to treat Pompe disease, as disclosed by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use the combined composition of the reference application and Kornfeld to treat Pompe disease, because Kornfeld discloses GAA can be used to treat Pompe disease via ERT.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/028827 in view of Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of Do.
The claims of the reference application and disclosure of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. The claims of the reference application do not recite a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding instant claim 6, Do discloses a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do discloses that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do discloses that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as disclosed by Kornfeld above. While Kornfeld and Do do not disclose a GAA wherein less than 40% of the N-glycans are complex, Do discloses that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as disclosed by Do, and therefore enzyme uptake by the M6P receptor, as disclosed by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do discloses rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the disclosures of Kornfeld and Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application, Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of the reference application, Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do discloses rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld discloses highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding instant claim 7, Do discloses no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
E. Claims 1-5 and 8-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/029413 (herein reference application) in view of Kornfeld.
Regarding instant claim 1, claim 1 of the reference application recites a method for treating Pompe disease comprising administering recombinant GAA. Under the broadest reasonable interpretation, the administration of recombinant GAA recited by the claim of the reference application is considered to correspond to a composition comprising GAA.
The claims of the reference application do not recite a composition comprising GAA wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylated lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding instant claim 1, Kornfeld discloses a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld discloses the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally discloses that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the claims of the reference application by replacing the GAA of the reference application with the GAA of Kornfeld to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the GAA of the reference application and the GAA of Kornfeld both correspond to GAA enzymes, and as such both are capable of being incorporated into compositions as described by the reference application and Kornfeld. Thus it would have been obvious to one of ordinary skill in the art to replace the GAA of the reference application with the GAA of Kornfeld, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Kornfeld relate to compositions and GAA.
In view of the results and disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the combined composition of the reference application and Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld discloses cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and discloses highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding instant claims 2-5, Kornfeld discloses the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not disclose that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and disclosure of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding instant claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claims 12-13, Kornfeld discloses the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld discloses enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally discloses ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to use the combined composition of the reference application and Kornfeld to treat Pompe disease, as disclosed by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use the combined composition of the reference application and Kornfeld to treat Pompe disease, because Kornfeld discloses GAA can be used to treat Pompe disease via ERT.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/029413 in view of Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of Do.
The claims of the reference application and disclosure of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. The claims of the reference application do not recite a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding instant claim 6, Do discloses a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do discloses that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do discloses that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as disclosed by Kornfeld above. While Kornfeld and Do do not disclose a GAA wherein less than 40% of the N-glycans are complex, Do discloses that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as disclosed by Do, and therefore enzyme uptake by the M6P receptor, as disclosed by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do discloses rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the disclosures of Kornfeld and Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application, Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of the reference application, Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do discloses rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld discloses highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding instant claim 7, Do discloses no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
F. Claims 1-5 and 8-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/645828 (herein reference application) in view of Kornfeld.
Regarding instant claim 1, claim 1 of the reference application recites a pharmaceutical composition comprising a recombinant GAA.
The claims of the reference application do not recite a composition comprising GAA wherein at least 50%of the total N-linked oligosaccharides of the GAA are phosphorylated.
Kornfeld relates to compositions comprising a modified GlcNAc-1-phosphotransferase (GNP) [title] with the enhanced ability to phosphorylated lysosomal enzymes [abstract] and uses for enzyme replacement therapy (ERT) wherein a produced replacement enzyme containing N-linked glycans with terminal mannose residues is taken up by macrophages via cell surface mannose residues in order to transport the replacement enzyme to lysosomes to function with good clinical results [para 0004]. Kornfeld further discloses that cell types other than macrophages use phosphorylated mannose (mannose 6-phosphate, or M6P) receptors to facilitate delivery of a replacement enzyme to lysosomes due to the lack of the macrophage mannose transport system [para 0005].
Regarding instant claim 1, Kornfeld discloses a method of increasing oligosaccharide phosphorylation of lysosomal enzymes such as GAA by co-expressing the lysosomal enzyme with a modified GNP in a cell [paras 0010 and 0012], as GNP phosphorylates mannose residues of the N-glycans of lysosomal enzymes such as GAA [para 0005]. Given a broadest reasonable interpretation, the cell of Kornfield is considered to correspond to a composition comprising GAA. While Kornfeld does not recite that 50% of the N-linked oligosaccharides of GAA are phosphorylated as recited in the claim, Kornfeld discloses the co-expression of the modified GNP with GAA can increase the amount of phosphorylation compared to a control up to 75% [para 0065]. According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Kornfeld additionally discloses that enzymes such as GAA that are highly phosphorylated will bind well to M6P receptors, and that enzymes that are poorly phosphorylated are limited in their effectiveness in ERT [para 0005]. Therefore Kornfeld identifies phosphorylation to be a result effective variable, which is a variable that achieves a recognized result (e.g., uptake via M6P receptors and effectiveness in ERT) according to MPEP 2144.05.II.B.
In view of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the claims of the reference application by replacing the GAA of the reference application with the GAA of Kornfeld to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the GAA of the reference application and the GAA of Kornfeld both correspond to GAA enzymes, and as such both are capable of being incorporated into compositions as described by the reference application and Kornfeld. Thus it would have been obvious to one of ordinary skill in the art to replace the GAA of the reference application with the GAA of Kornfeld, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both the reference application and Kornfeld relate to compositions and GAA.
In view of the results and disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % phosphorylation of N-linked oligosaccharides in GAA to arrive at the claimed invention, because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and because Kornfeld establishes the result-effective variable of phosphorylation of GAA which affects the results of binding to M6P receptors in ERT.
One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to modify the combined composition of the reference application and Kornfeld to achieve the amount of phosphorylated N-linked oligosaccharides, because Kornfeld discloses cell types lacking a mannose transport system instead use M6P receptors to bring in replacement enzymes in ERT, and discloses highly phosphorylated replacement enzymes bind well to M6P receptors.
Regarding instant claims 2-5, Kornfeld discloses the modified GNP increases the formation of glycans with two M6P residues that results in higher affinity for the M6P receptors [para 0026], which is considered to correspond to bis-phosphorylation of GAA. While Kornfeld does not disclose that at least 25% (claim 2) of the N-linked oligosaccharides on GAA are bis-phosphorylated, at least 50% (claim 3) of the N-linked oligosaccharides on GAA are bis-phosphorylated, on average each GAA molecule comprises at least 2 bis-phosphorylated N-linked glycans (claim 4), or less than 8% of the GAA comprises non-phosphorylated N-linked glycans (claim 5), Kornfeld establishes the result-effective variable of bis-phosphorylation, which is a variable that achieves a recognized result (e.g., higher affinity for M6P receptors, and therefore increased effectiveness in ERT) according to MPEP 2144.05.II.B. Therefore in view of the results and disclosure of Kornfeld, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to achieve the claimed % bis-phosphorylation of N-linked oligosaccharides of GAA of claims 2-4, as Kornfeld establishes the result-effective variable of bis-phosphorylation of GAA affects the results of M6P receptor affinity in ERT. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the composition Kornfeld to achieve and the claimed % of non-phosphorylated GAA of claim 5, as Kornfeld establishes the result-effective variable of phosphorylation of GAA affects the results of binding to M6P receptors in ERT as discussed in the rejection of claim 1 above.
Regarding instant claim 8, the limitation of “comprising less than 5 nanomolar affinity for CIMPR” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of comprising less than 5 nanomolar affinity for CIMPR, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 9, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 10, the limitation of “comprising 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa” in the recited tissues is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the property of 0.1 to 5-fold greater ability to reduce glycogen compared to alglucosidase alfa in the recited tissues, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claim 11, the limitation of “capable of being endogenously hydrolyzed” is considered to be a functional limitation or a property of the claimed composition, and as such does not structurally limit the claimed composition. As the combined composition of the reference application and Kornfeld satisfies the structural limitations of the composition set forth in the claims, it is considered to have the capability of being endogenously hydrolyzed, as MPEP 2112.01.I states where the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are presumed to be inherent.
Regarding instant claims 12-13, Kornfeld discloses the limitations of the composition of claim 1 as discussed above. Additionally, Kornfeld discloses enzyme replacement therapy (ERT) can be used to treat lysosomal storage diseases, wherein such enzymes used comprise GAA for use in the treatment of Pompe disease via ERT [para 0067]. Kornfeld additionally discloses ERT is a lifelong therapy wherein products are administered intravenously either through a peripheral line or central access device and [para 0067].
In view of the disclosure of Kornfeld, it would have been obvious for one of ordinary skill in the art before the effective filing date to use the combined composition of the reference application and Kornfeld to treat Pompe disease, as disclosed by Kornfeld, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated, and would have had a reasonable expectation of success, to use the combined composition of the reference application and Kornfeld to treat Pompe disease, because Kornfeld discloses GAA can be used to treat Pompe disease via ERT.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/645828 in view of Kornfeld as applied to claims 1-5 and 8-13 above, and further in view of Do.
The claims of the reference application and disclosure of Kornfeld as applied to claims 1-5 and 8-13 are discussed above. The claims of the reference application do not recite a composition wherein less than 40% of the GAA glycans comprise complex type N-glycans.
Do relates to selection of high M6P recombinant proteins [title] corresponding to recombinant human lysosomal proteins with a high content of M6P residues and their uses [abstract], particularly as a treatment option for Pompe disease via ERT comprising recombinant human GAA [para 0006].
Regarding instant claim 6, Do discloses a recombinant human lysosomal protein wherein 40% of the total N-glycans are complex type N-glycans [para 0115], and wherein the recombinant protein is rhGAA [claim 22]. Do discloses that rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen [para 0008]. Do discloses that rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes [para 0008], indicating the importance of high levels of phosphorylation for the delivery of the enzyme to cells, and subsequent success in ERT as disclosed by Kornfeld above. While Kornfeld and Do do not disclose a GAA wherein less than 40% of the N-glycans are complex, Do discloses that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR [para 0009], therefore establishing complex N-glycans as a result-effective variable, which is a variable that achieves a recognized result (e.g., delivery to lysosomes via M6P receptor binding) according to MPEP 2144.05.II.B. As the amount of complex N-glycans directly affects the amount of possible phosphorylation as disclosed by Do, and therefore enzyme uptake by the M6P receptor, as disclosed by Kornfeld, one of ordinary skill in the art would be motivated to decrease the amount of complex N-glycans present in a composition in order to increase the potential cellular uptake of GAA.
In view of Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application and Kornfeld to include the rhGAA of Do to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to include the rhGAA of Do because Do discloses rhGAA with two M6P groups on the same glycan has high affinity of approximately 2 nM to CIMPR, and once inside the lysosome the rhGAA can enzymatically degrade glycogen. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
In view of the disclosures of Kornfeld and Do, it would have been obvious for one of ordinary skill in the art before the effective filing date to modify the combined composition of the reference application, Kornfeld and Do to achieve the claimed % complex N-glycans in GAA to arrive at the claimed invention, because Do establishes the result-effective variable of % complex N-glycans that affects the results of M6P binding through lack of potential phosphorylation, which is consistent with the result-effective variable established by Kornfeld of GAA phosphorylation affecting the results of binding to M6P receptors in ERT. One of ordinary skill in the art would have been motivated to modify the combined composition of the reference application, Kornfeld and Do to achieve the amount of complex N-glycans in GAA, because Do discloses rhGAA with low levels of M6P target muscle cells poorly and result in inferior delivery of rhGAA to the lysosomes, and that since complex N-glycans present in rhGAA are not phosphorylated they have no affinity for CIMPR, and Kornfeld discloses highly phosphorylated enzymes such as GAA bind well to M6P receptors and are therefore effective in ERT applications. One of ordinary skill in the art would have had a reasonable expectation of success because Kornfeld and Do relate to GAA with high phosphorylation used in ERT to treat Pompe disease.
Regarding instant claim 7, Do discloses no more than 1, 2, 3, 4, 5, 6, 7% of the total N-glycans of rhGAA are hybrid N-glucans [para 0115].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Status of the Application:
Claims 1-13 are pending.
Claims 1-13 are rejected.
No claim is in condition for allowance.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
Prosecution Insights