DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 36-37 and 40 are cancelled. Claims 1-35, 38-39, and 41-43 are pending.
Claims 4, 19-20, and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/10/2026.
Applicant elected the following species, drawn to a pharmaceutical composition:
with respect to the nonionic surfactants, a polysorbate and poloxamer are elected, polysorbate 80 being elected as polysorbate and polyoxyethylene(160) polyoxypropylene(30) glycol being elected as the poloxamer;
"with" a neutral salt, a disaccharide, and a buffering agent, wherein sodium chloride is elected as the neutral salt, sucrose is elected as the disaccharide, and the citrate buffer is elected as the buffer agent;
with respect to a method of combining an antibody and a lysosomal enzyme, Fab antibody of humanized anti-human transferrin receptor (hTfR) antibody as the antibody, human α-L-iduronidase as the lysosomal enzyme, and a fusion protein of the antibody with the human α-L-iduronidase as the fusion protein, wherein, in the fusion protein, the antibody light chain includes the amino acid sequence set forth as SEQ ID NO: 22, the antibody heavy chain includes the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain being bonded at the C-terminus with human α-L-iduronidase having the amino acid sequence set forth as SEQ ID NO: 6, via the amino acid sequence set forth as SEQ ID NO: 4.
Claims 1-3, 5-18, 21-33, 35, 38-39, and 41-43 are currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/JP2022/013755 (filed on 03/23/2022) which claims benefit of Japan Application No. JP2021-049485 (filed on 03/24/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Applicant cannot rely upon the certified copy of the foreign priority application because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Because an English translation of the certified copy of the foreign priority application has not been made of the record, the examiner cannot establish whether or not what is claimed in the instant application was properly disclosed in the foreign priority application. Therefore, the benefit to the foreign priority application date is not granted.
Claims 1-3, 5-33, 35, 38-39, and 41-43 have an effective filing date of 03/23/2022 corresponding to PCT/JP2022/013755.
Information Disclosure Statement
The information disclosure statements filed on 12/19/2023 and 04/11/2025 have been considered. Signed copies are enclosed.
Notably, the disclosure statements filed list Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 29-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 29 is drawn to an aqueous composition comprising two different nonionic surfactants and a fusion protein of an antibody and a lysosomal enzyme, wherein the antibody recognizes as antigen a molecule present on the surfaces of vascular endothelial cells.
As such, claim 29 is drawn to a genus of antibodies that specifically bind to an antigen on any molecule present on the surfaces of vascular endothelial cells. Molecules on the surfaces of endothelial are varied, including but not limited to proteoglycans, glycoproteins, and cell adhesion molecules.
The instant specification defines “antibody” as “full length antibodies… [and] also any form of antigen-binding fragment (antibody fragment) lacking part of the full length antibodies” (¶ 0046). Furthermore, antigen-binding fragments “include heavy chain antibodies, light chain antibodies, VHH and VNAR, as well as those lacking portions thereof” (¶ 0046).
Thus, as instantly claimed, the antibody of claim 29 can comprised fewer than 6 parental CDRs, and may, more specifically, comprise no CDRs. The instant specification discloses a humanized anti-human transferrin receptor (hTfR) Fab antibody comprising a light chain having the amino acid sequence set forth as SEQ ID NO: 22 and a heavy chain having the amino acid sequence set forth as SEQ ID NO: 23 (¶ 0199). A Fab antibody includes 6 CDRs. Transferrin receptors are known to be is present on human cerebrovascular endothelial cells.
However, Applicant is claiming a large and structurally diverse genus of antibodies that can bind to an antigen on any molecule present on the surfaces of vascular endothelial cells, wherein the antibody can comprise fewer than 6 parental CDRs or potentially no CDRs. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) which isolated CDRs would specifically bind an antigen on a molecule present on the surfaces of vascular endothelial cells, (ii) how many CDRs/what combinations of the recited CDRs yield antibodies capable of specifically binding said antigen, and (iii) the identity of said antigen (i.e. what molecule on the surface of vascular endothelial cells the antibody binds).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed antibody and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed a species within the genus claimed (humanized anti-hTfR Fab antibody comprising SEQ ID NOs: 22-23). However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of one adequately described species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind an antigen on a molecule present on the surfaces of vascular endothelial cells. It is well-known in the art that antibodies generally comprise six parental CDRs. The amino acid sequences of the CDRs are hypervariable, and the amino acid residues contained within the six CDRs determine the antigen specificity of a particular antibody. Absent a description of the at least minimal structural features correlating with a functional ability to bind an antigen on a molecule present on the surfaces of vascular endothelial cells which are shared by members of a genus of antibodies commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which CDR amino acid sequences (or combinations thereof) may be combined such that the resultant antibody comprises six CDRs that confer the ability to bind an antigen on a molecule present on the surfaces of vascular endothelial cells and the identity of said antigen.
Although screening techniques can be used to antibodies that possess the ability to bind an antigen on a molecule present on the surfaces of vascular endothelial cells, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the difficulty associated with predicting CDR combinations that yield antibodies capable of binding an antigen on a molecule present on the surfaces of vascular endothelial cells, and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of claim 29. Claim 29 fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Claims 30-32 are included in this rejection as they incorporate and/or depend on claim 29.
Claims 1-3, 5-18, 21-33, 35, 38-39, and 41-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an aqueous or lyophilized pharmaceutical composition comprising a fusion protein of a humanized anti-human transferrin receptor (hTfR) Fab antibody and the human α-L-iduronidase, polysorbate 80, and polyoxyethylene(160) polyoxypropylene(30) glycol, does not reasonably provide enablement for an aqueous or lyophilized pharmaceutical composition comprising any protein having physiological activity and any two different nonionic surfactants. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention
Claim 1 is drawn to “[a]n aqueous pharmaceutical composition or lyophilized pharmaceutical composition comprising a protein having physiological activity, and two different nonionic surfactants.” (lines 1-3).
The field of invention resides in the fields of biochemistry and protein chemistry, complex and unpredictable arts. The term “a protein having physiological activity” defines the protein by a functional definition rather than a structural one. Claim 1, therefore, encompasses thousands of proteins with different structures and functions, including but not limited to antibodies to detect foreign particles, enzymes to carry out chemical reactions, hormones to transmit signals, and structural components to support cells (MedlinePlus Genetics, What are proteins and what do they do?, National Institutes of Health, 2021; Pg. 1, Table 1). A protein’s structure cannot be accurately be predicted from its function alone.
In addition, not all proteins having a physiological activity can be isolated for use in a composition. For example, netrin-1, a guidance cue for axons, “appears to aggregate and to precipitate out of solution” and thus studies of netrin-1 rely on derivatives of the protein (Keino-Masu et al., Deleted in Colorectal Cancer (DCC) Encodes a Netrin Receptor, Cell, Volume 87, Issue 2, 1996, Pages 175-185; Pg. 179, column 2, ¶ 1). Claim 1 encompasses proteins having physiological activity that are not stable in a composition.
The complexity of the claimed subject matter is further exacerbated by the inclusion of nonionic surfactants of unknown identity. Nonionic surfactants are varied, including polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, and polysorbate 85, poloxamer 188, and poloxamer 407. Protein-surfactant interactions are highly protein-specific, with some of these surfactants causing damage to proteins. For example, Khan et al. teach “surfactants may present liabilities that could destabilize proteins and/or hinder reproducible drug product manufacturing. Polysorbates are known to degrade via oxidation and hydrolysis and cause oxidative damage to the protein via production of reactive oxygen species” (Key interactions of surfactants in therapeutic protein formulations: A review, European Journal of Pharmaceutics and Biopharmaceutics, Volume 97, Part A, 2015, Pages 60-67; Pg. 61, column 2, ¶ 2). Claim 1 encompasses nonionic surfactants that are not suitable for all proteins having physiological activity in a composition.
Consequently, claim 1 is directed to complex and unpredictable fields, where the successful formulation of all proteins having physiological activity with any two different nonionic surfactants cannot be readily extrapolated. As such, claim 1 generally reads on an aqueous or lyophilized pharmaceutical composition comprising any protein having physiological activity and any two different nonionic surfactants, the full scope of which is not enabled by the method as instantly claimed.
(2) The state of the prior art
US 20190338043 A1 teaches a fusion protein of a humanized anti-hTfR Fab antibody and the human α-L-iduronidase has physiological activity (¶ 0247, “fusion protein between the humanized anti-hTfR [anti-human transferrin receptor] antibody of the present invention and a different protein [A] is a fusion protein consisting of the different protein [A]”; ¶ 0128, “the antibody is Fab antibody”; ¶ 0121, “protein [A] is… human α-L-iduronidase”; ¶ 0246, “protein [A] linked to the antibody also exhibits the protein's own physiological activity”).
However, prior art teaches proteins having physiological activity are varied, including antibodies to detect foreign particles, enzymes to carry out chemical reactions, hormones to transmit signals, and structural components to support cells (MedlinePlus Genetics, What are proteins and what do they do?, National Institutes of Health, 2021; Pg. 1, Table 1).
Not all proteins having a physiological activity can be isolated for use in a composition. For example, netrin-1, a guidance cue for axons, “appears to aggregate and to precipitate out of solution” and thus studies of netrin-1 rely on derivatives of the protein (Keino-Masu et al., Deleted in Colorectal Cancer (DCC) Encodes a Netrin Receptor, Cell, Volume 87, Issue 2, 1996, Pages 175-185; Pg. 179, column 2, ¶ 1).
Prior art teaches that nonionic surfactants such as polysorbates and poloxamers were known and used in aqueous and lyophilized protein compositions (US 20190338043 A1; ¶ 0751, “nonionic surfactants may preferably be used. Examples of such nonionic surfactants include polysorbate and poloxamer”; ¶ 0750, “proteins… can be provided to medical facilities as pharmaceutical agents in such forms of lyophilized product or aqueous preparation”).
However, nonionic surfactants are varied, including polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, and polysorbate 85, poloxamer 188, and poloxamer 407. Some of these surfactants cause damage to proteins. For example, Khan et al. teach “surfactants may present liabilities that could destabilize proteins and/or hinder reproducible drug product manufacturing. Polysorbates are known to degrade via oxidation and hydrolysis and cause oxidative damage to the protein via production of reactive oxygen species” (Key interactions of surfactants in therapeutic protein formulations: A review, European Journal of Pharmaceutics and Biopharmaceutics, Volume 97, Part A, 2015, Pages 60-67; Pg. 61, column 2, ¶ 2).
Therefore, it is unclear how such broad classes of molecules, including (i) proteins having physiological activity, not all known to be purifiable, and (i) nonionic surfactants with varied stability profiles would behave in an aqueous or lyophilized composition.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art,
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
While the use of proteins having physiological activity and nonionic surfactants in an aqueous or lyophilized pharmaceutical composition is well known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the use of any protein having physiological activity and any two different nonionic surfactants in an aqueous or lyophilized pharmaceutical composition within the scope of claim 1 is not predictable.
The predictability of applying any protein having physiological activity and any two different nonionic surfactants in an aqueous or lyophilized pharmaceutical composition would be low given that 1) proteins having physiological activity are varied, not all known to be purifiable, 2) nonionic surfactants are varied, with different stability profiles, 3) it is unclear what combination of proteins and surfactants maintain physiological activity, and 4) the instant application fails to demonstrate aqueous or lyophilized pharmaceutical compositions with all possible combinations of protein having physiological activity and two different nonionic surfactants (the predictability or unpredictability of the art).
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The specification shows an aqueous or lyophilized pharmaceutical composition of a fusion protein of a humanized anti-hTfR Fab antibody and the human α-L-iduronidase with nonionic surfactants polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol (Example 7, ¶ 0241, “aqueous pharmaceutical compositions” and “poloxamer 188, polysorbate 80 and humanized anti-hTfR antibody-hIDUA [human α-L-iduronidase]”; Example 13, ¶ 0252, “the aqueous pharmaceutical composition comprising humanized anti-hTfR antibody-hIDUA was filled into a glass vial… and lyophilized”). Prior art, specifically US 20190338043 A1, also provides composition as well (see state of the prior art section).
The specification does not provide any additional examples or guidance on how to use proteins outside of humanized anti-hTfR antibody-hIDUA and nonionic surfactants outside of polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol as recited in the claim (the amount of direction or guidance presented and the presence or absence of working examples). The instant application is not enabled for all possible combinations of proteins having physiological activity and two different nonionic surfactants.
The amount of experimentation would not be reasonable because it would require determining which protein having physiological activity and nonionic surfactants to use in combination to for a stable aqueous or lyophilized composition. It is not routine to determine how such broad classes of molecules, including (i) proteins having physiological activity, not all known to be purifiable, and (i) nonionic surfactants with varied stability profiles would behave in an aqueous or lyophilized composition.
Undue experimentation would be required to determine whether proteins having physiological activity and nonionic surfactants would be suitable in a pharmaceutical composition (the quantity of the experimentation, see MPEP 2164.06).
(5) The breadth of the claims
The scope of claim 1 is extremely broad; it recites multiple proteins having physiological activity and nonionic surfactants that require the specification of the instant application to provide support for the entire scope of the claim. A protein having physiological activity encompasses thousands of proteins with different structures and functions, including but not limited to antibodies to detect foreign particles, enzymes to carry out chemical reactions, hormones to transmit signals, and structural components to support cells, some of which are not stable in a composition (see nature of the invention and state of the prior art).
In addition, nonionic surfactants are varied, including polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, and polysorbate 85, poloxamer 188, and poloxamer 407. Protein-surfactant interactions are highly protein-specific, with some of these surfactants causing damage to proteins (see nature of the invention and state of the prior art).
Claim 1 is directed to complex and unpredictable fields, where the successful formulation of all proteins having physiological activity with any two different nonionic surfactants cannot be readily extrapolated from the limited number of disclosed examples in the instant application. The specification fails to show that a person having ordinary skill in the art could make the recited compositions without undue experimentation.
Evidence of an aqueous or lyophilized pharmaceutical composition of a fusion protein of a humanized anti-hTfR Fab antibody and the human α-L-iduronidase with nonionic surfactants polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol in provided in the specification of the instant application and in the prior art.
Therefore, an aqueous or lyophilized pharmaceutical composition comprising a fusion protein of a humanized anti-hTfR Fab antibody and the human α-L-iduronidase, polysorbate 80, and polyoxyethylene(160) polyoxypropylene(30) glycol is supported. An aqueous or lyophilized pharmaceutical composition comprising any protein having physiological activity and any two different nonionic surfactants is not supported.
Claim 1 is not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to make aqueous or lyophilized pharmaceutical compositions comprising all possible combinations of a protein having physiological activity and two different nonionic surfactants with a predictability of success for the reasons outlined above. Claims 2-3, 5-18, 21-33, 35, 38-39, and 41-43 are included in this rejection as they depend on and/or incorporate claim 1.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-14, 18, 21-33, 35, and 41-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 10, the phrase "two or more of the same" renders the claim indefinite because it is unclear what disaccharides are being referred to. The phrase "two or more of the same" could refer to (i) two instances of a single disaccharide (e.g. trehalose and trehalose), (ii) combinations of two or more different disaccharides selected from trehalose, sucrose, maltose, and lactose, or (iii) combinations of two or more different disaccharides selected from trehalose, sucrose, maltose, lactose, and similar disaccharides not mentioned by name.
For the purposes of claim interpretation, the phrase "two or more of the same" will be treated as combinations of two or more different disaccharides selected from trehalose, sucrose, maltose, and lactose.
Claims 9 and 12-14 recite the limitation "the neutral salt" in line 2 of claims 9 and 12-14. Claims 10 and 12-14 recite the limitation "the disaccharide" in line 2 of claims 10 and line 3 of claims 12-14. Claims 11 and 12-14 recite the limitation "the buffering agent" in line 2 of claims 11 and line 3 of claims 12-14. There is insufficient antecedent basis for these limitations in the claims.
For the purposes of claim interpretation, claims 9-14 will be treated as dependent on claim 2.
Claim 18 recites the limitation “the fusion protein” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claims 21-33 and 35 are include is this rejection as they incorporate and/or depend on claim 18.
Claims 41-43 recite the limitations “the polymer” and “the content ratio” in line 2 of claims 41-43. There is insufficient antecedent basis for these limitations in the claims.
Regarding claims 41-43, the phrase "the polymer" renders the claim indefinite because it is unclear what polymer is being referred to. The specification does not give a definition for polymer.
For the purposes of claim interpretation, “the polymer” will be treated as multimers of the fusion protein, said protein delineated in the species election.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 5-6, 18, 21-33, and 35 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 20190338043 A1 (referred to as US ’043, filed 2017-12-26, published 2019-11-07).
Claims 1, 3, 5, 18, 21-28, 33, and 35
US ‘043 teaches a fusion protein having physiological activity of an antibody and a lysosomal enzyme with a Fab antibody of humanized anti-hTfR antibody as the antibody and human α-L-iduronidase as the lysosomal enzyme (¶ 0247, “fusion protein between the humanized anti-hTfR [anti-human transferrin receptor] antibody of the present invention and a different protein [A] is a fusion protein consisting of the different protein [A]” (instant claims 18 and 27); ¶ 0128, “the antibody is Fab antibody” (instant claims 28 and 33); ¶ 0121, “protein [A] is… human α-L-iduronidase” (instant claims 24-26); ¶ 0246, “protein [A] linked to the antibody also exhibits the protein's own physiological activity” (instant claim 1)).
US’ 043 further teaches the C-terminus of heavy chain of the humanized anti-hTfR antibody is bonded to human α-L-iduronidase via a linker of SEQ ID NO: 4 (¶ 0136, “the heavy chain of the antibody is linked, on the C-terminal side thereof and via the amino acid sequence consisting of three consecutively linked amino acid sequences each set forth as SEQ ID NO: 3, to the human α-L-iduronidase” ; SEQ ID NO: 3 of US ‘043 is GGGGS and three repeats of this sequence produces SEQ ID NO: 4 of the instant application (instant claims 21-23)).
US ‘043 further teaches SEQ ID NOs: 22-23 (disclosed as SEQ ID NOs: 23 and 61 respectively in US ‘043) for the humanized anti-hTfR antibody and SEQ ID NO: 6 for human α-L-iduronidase (disclosed as SEQ ID NO: 75 in US ‘043 ) (instant claim 35).
US ‘043 further teaches an aqueous pharmaceutical composition or lyophilized pharmaceutical composition of the fusion protein (¶ 0750, “proteins… conjugated with the anti-hTfR antibody of the present invention can be provided to medical facilities as pharmaceutical agents in such forms of lyophilized product or aqueous preparation”) (instant claim 1).
US ‘043 further teaches the aqueous pharmaceutical composition of the fusion protein contains the nonionic surfactants, polysorbate 80 as a polysorbate and polyoxyethylene(160) polyoxypropylene(30) glycol as a poloxamer (¶ 0751, “in the aqueous preparation… nonionic surfactants may preferably be used. Examples of such nonionic surfactants include polysorbate and poloxamer”; ¶ 0751, “Among polysorbates, polysorbate 20 and polysorbate 80 are preferably used” and “As poloxamer… polyoxyethylene[160] polyoxypropylene[30] glycol is particularly preferred” (instant claims 1, 3, and 5)).
Claim 6
US ‘043 further teaches the nonionic surfactants polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol both have concentrations of 0.1-0.5 mg/mL (¶ 0751, “the concentration of nonionic surfactant contained in the aqueous preparation is… 0.1-0.5 mg/mL”) (instant claim 6).
Claims 29-32
US ‘043 further teaches the antibody of the fusion protein recognizes as antigen a molecule, specifically transferrin receptor, present on human cerebrovascular endothelial cells (¶ 007, “Examples of those membrane proteins which occur on the endothelial cells of the brain capillaries include receptors for… transferrin” (instant claims 29-31); ¶ 0247, “anti-hTfR [anti-human transferrin receptor] antibody” (instant claim 32)).
Accordingly, claims 1, 3, 5-6, 18, 21-33, and 35 are anticipated by US ‘043.
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.
Claims 2 and 9-14 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190338043 A1 (referred to as US ‘043, filed 2017-12-26, published 2019-11-07) in view of EP 3589318 A1 (referred to as EP ‘318, published 2020-01-08) as evidenced by National Center for Biotechnology Information (PubChem Compound Summary for CID 5234, Sodium Chloride, 2026).
Claims 2 and 9-11 (claims 9-11 treated as dependent on claim 2, see 112[b] section)
US ‘043 teaches the aqueous pharmaceutical composition comprising a fusion protein having physiological activity and two different nonionic surfactants, polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol, as delineated in the 102 rejection of claim 1.
US ‘043 further teaches the aqueous pharmaceutical composition comprises sodium chloride (NaCl) and citrate buffer (¶ 0750, “the pharmaceutical agents is dissolved in a solution containing… an isotonizer”; ¶ 0751, “sodium chloride… may be preferably used alone or in combination as an isotonizer”; ¶ 0944, “purified anti-TfR antibody fusion protein of [human α-L-iduronidase] was diluted to an appropriate concentration with a 50 mM citrate buffer solution”).
US’ 043 does not teach the inclusion of sucrose in the aqueous pharmaceutical composition.
EP ‘318 teaches “antibody formulation” (¶ 0001) comprising NaCl (¶ 0020, “invention thus further provides a formulation comprising… a salt”; ¶ 0022, “the salt is NaCl”), sucrose (¶ 0093, “The formulations described herein suitably comprise a sugar, for example, but not limited to…sucrose”), citrate buffer (¶ 0087, “Exemplary buffers for use in the formulations provided herein include, but are not limited to… citrate”), polysorbate 80 (¶ 0030, “the formulation further comprises a surfactant… [such as] polysorbate-80”), and polyoxyethylene(160) polyoxypropylene(30) glycol (¶ 0095, “Pharmaceutically acceptable surfactants like… poloxamer 188”). Please note the specification of the instant application states, “Polyoxyethylene(160) polyoxypropylene(30) glycol is synonymous with poloxamer 188” (¶ 0075).
EP ‘318 further teaches the inclusion of sucrose “improve[s] tonicity” (¶ 0024).
EP ‘318 does not teach the fusion protein of claim 1.
Antibody formulations containing NaCl, sucrose, citrate buffer, polysorbate 80, and polyoxyethylene(160) polyoxypropylene(30) glycol were known and used prior to the effective filing date of the application. The inclusion of sucrose is routine. In addition, both US ‘043 and EP ‘318 are in analogous arts (i.e. formulations of antibodies or fusion proteins containing antibodies). Since EP ‘318 teaches the inclusion of sucrose improves tonicity in an antibody formulation, there is motivation for using this excipient.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. the inclusion of sucrose improves tonicity in an antibody formulation as taught in EP ‘318) would have led one of ordinary skill to modify the prior art reference (i.e. the aqueous pharmaceutical composition comprising a fusion protein having physiological activity comprising NaCl, citrate buffer, polysorbate 80, and polyoxyethylene[160] polyoxypropylene[30] glycol as taught in US ‘043) to arrive at the claimed invention. There is a reasonable expectation of success as EP ‘318 and the instant application teach the same excipients, known and used prior to the effective filing date of the application. The inclusion of sucrose is routine in an antibody formulation. In addition, both US ‘043 and EP ‘318 are in analogous arts (i.e. formulations of antibodies or fusion proteins containing antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to include sucrose in an antibody formulation as taught in EP ‘318 in the aqueous pharmaceutical composition comprising a fusion protein having physiological activity comprising NaCl, citrate buffer, polysorbate 80, and polyoxyethylene(160) polyoxypropylene(30) glycol as taught in US ‘043.
Claims 12-14 (treated as dependent on claim 2, see 112[b] section)
EP ‘318 further teaches the excipients in an antibody formulation have the following concentrations in weight/volume wherein EP ‘318 teaches:
0.1 mg/mL polysorbate 80 (¶ 0097, “the formulations described herein comprise a surfactant… about 0.01% [w/v]”; equivalent to 0.1 mg/mL as calculated below; claims 12-14),
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2.9-5.8 mg/mL to NaCl (¶ 0081, “The concentration of the ionic excipient, suitably salt, in the pharmaceutical formulations described herein is generally in the range of… about 50 mM to about 100 mM”; equivalent to about 2.9-5.8 mg/mL as calculated below),
National Center for Biotechnology Information states the molecular weight of NaCl is 58.44 g/mol (Pg. 1).
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80 mg/mL sucrose (¶ 0094, “the amount of sugar… in a formulation described herein is… about 8 % [w/v]”; equivalent to 80 mg/mL as calculated below; claims 12-14), and
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15 mM citrate buffer (¶ 0088, “The concentration of a buffer… in the pharmaceutical formulations described herein is generally… about 15 mM”; claims 12-14).
EP ‘318 teaches the antibody formulation comprising NaCl, sucrose, citrate buffer, polysorbate 80, and polyoxyethylene(160) polyoxypropylene(30) glycol for the purposes of “stabilizing the antibody” (¶ 0012, applicable to NaCl), “improv[ing] tonicity” (¶ 0024, applicable to sucrose), “maintaining the pH” (¶ 0087, applicable to citrate buffer), and “solubilizing” (¶ 0095, applicable to polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol).
Regarding claims 12-14, EP ‘318 does not teach that NaCl has a concentration of 0.3-1.2 mg/mL (claim 12), 0.5-1.0 mg/mL (claim 13), and 0.7-0.9 mg/mL (claim 14).
MPEP 2144.05(II)(A) states: "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. concentrations of NaCl, sucrose, citrate buffer, polysorbate 80, and polyoxyethylene[160] polyoxypropylene[30] glycol), so as to achieve optimal effect and maximal benefit (i.e. stabilize the antibody, improve tonicity, maintain pH, and solubilize as taught in EP ‘318). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of excipient concentrations would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed excipient concentrations to achieve them without undue experimentation in order to stabilize the antibody, improve tonicity, maintain pH, and solubilize as taught in EP ‘318.
Accordingly, claims 2 and 9-14 are rendered obvious over US ‘043 in view of EP ‘318 as evidenced by National Center for Biotechnology Information.
Claims 7-8 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190338043 A1 (referred to as US ‘043, filed 2017-12-26, published 2019-11-07) in view of EP 3589318 A1 (referred to as EP ‘318, published 2020-01-08).
Claims 7-8
US ‘043 teaches the aqueous pharmaceutical composition comprising a fusion protein having physiological activity and two different nonionic surfactants, polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol, as delineated in the 102 rejection of claims 1 and 3.
US ‘043 further teaches the nonionic surfactants polyoxyethylene(160) polyoxypropylene(30) glycol has a concentration of 0.1-0.5 mg/mL (¶ 0751, “the concentration of nonionic surfactant contained in the aqueous preparation is… 0.1-0.5 mg/mL”; applicable to claim 7).
US ‘043 does not teach the exact excipient concentrations of polysorbate 80 and/or polyoxyethylene(160) polyoxypropylene(30) glycol as recited in claims 7-8 (see below for more information).
Claim 7: The concentration of the polysorbate is 0.025 to 1.0 mg/mL.
Claim 8: The concentration of the polysorbate is 0.05 to 0.15 mg/mL and the concentration of the poloxamer is 0.15 to 0.45 mg/mL.
EP ‘318 teaches “antibody formulation” (¶ 0001) comprising polysorbate 80 (¶ 0030, “the formulation further comprises a surfactant… [such as] polysorbate-80”) and polyoxyethylene(160) polyoxypropylene(30) glycol (¶ 0095, “Pharmaceutically acceptable surfactants like… poloxamer 188”). Please note the specification of the instant application states, “Polyoxyethylene(160) polyoxypropylene(30) glycol is synonymous with poloxamer 188” (¶ 0075).
EP ‘318 teaches the excipients in an antibody formulation have the following concentrations:
0.1 mg/mL polysorbate 80 (¶ 0097, the formulations described herein comprise a surfactant… about 0.01% [w/v]”; equivalent to 0.1 mg/mL as calculated below; claims 7-8),
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EP ‘318 teaches the antibody formulation comprising polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol for the purpose of “solubilizing” (¶ 0095, applicable to both polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol).
MPEP 2144.05(II)(A) states: "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. concentrations of polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol), so as to achieve optimal effect and maximal benefit (i.e. solubilize as taught in EP ‘318). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of excipient concentrations would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed excipient concentrations to achieve them without undue experimentation in order to solubilize as taught in EP ‘318.
Claims 15-17
US ‘043 further teaches the pH of the aqueous pharmaceutical formulation is 5.5-7.2 (¶ 0751, “pH of the aqueous preparation adjusted with a buffer is preferably 5.5-7.2).
US ‘043 does not teach the pH is 4.5-6.5 (claim 15), 5.0-6.0 (claim 16), and 5.2-5.8 (claim 17). These ranges as stated in claims 15-17 overlap with the range given in US ‘043.
EP ‘318 further teaches “[a]t more acidic pH, an increased rate of fragmentation, reduced conformational stability and increased aggregation can be observed. At more basic pH, the potential for increased oxidation, deamidation and fragmentation and incompatibility with glass containers are present” (¶ 0004). Therefore, pH is a result effective variable that can be optimized for antibody stability.
EP ‘318 does not teach the pH is 4.5-6.5 (claim 15), 5.0-6.0 (claim 16), and 5.2-5.8 (claim 17).
MPEP 2144.05(II)(A) states: "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. pH), so as to achieve optimal effect and maximal benefit (i.e. stabilize the antibody as taught in EP ‘318). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of the pH would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed pHs to achieve them without undue experimentation in order to stabilize the antibody as taught in EP ‘318.
Accordingly, claims 7-8 and 15-17 are rendered obvious over US ‘043 in view of EP ‘318.
Claims 38-39 and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190338043 A1 (referred to as US ‘043, filed 2017-12-26, published 2019-11-07) in view of US 20180099049 A1 (referred to as US ‘049, filed 2017-10-06, published 2018-04-12) as evidenced by Foxx Life Sciences (Borosil® Reusable Amber Light-Blocking Round Glass Media Storage Bottles with Easy to Open GL 45 Autoclavable PP Cap, Pouring Ring, and Enamel Marking Spot, 3L, 2/CS, 2026).
Claim 38
US ‘043 teaches the aqueous pharmaceutical composition comprising a fusion protein having physiological activity and two different nonionic surfactants, polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol, with concentrations of 0.1-0.5 mg/mL as delineated in the 102 rejection of claims 1, 3, and 6.
US ‘043 does not teach the aqueous composition is capable of being lyophilized.
US ‘049 teaches the inclusion of polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol in “pre-lyophilized protein-containing aqueous solution” (¶ 0067, polysorbate 80 and poloxamer 188 included as surfactants). Please note the specification of the instant application states, “Polyoxyethylene(160) polyoxypropylene(30) glycol is synonymous with poloxamer 188” (¶ 0075).
US ‘049 further teaches the aqueous composition of a protein, specifically an antibody, is capable of being lyophilized (¶ 0027, “the pharmaceutically acceptable lyophilized cake is manufactured by combining a protein, a buffer, a nonionic surfactant, and one or more stabilizers in water to make a pre-lyophilized aqueous solution. The solution is then freeze-dried to make a cake… The freeze-dried [lyophilize] protein is in a ‘solid state’”; ¶ 0023, “the protein is a therapeutic antibody”).
US ‘049 further teaches “[l]yophilization (freeze drying under controlled conditions) is commonly used for long-term storage of proteins” (¶ 0003).
Lyophilization of an aqueous composition containing antibodies and surfactants was known and used prior to the effective filing date of the application. In addition, both US ‘043 and US ‘049 are in analogous arts (i.e. compositions of antibodies or fusion proteins containing antibodies). Since US ‘049 teaches lyophilization is commonly used for long-term storage of proteins, there is motivation for lyophilizing an aqueous composition containing a protein.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. lyophilization is commonly used for long-term storage of proteins as taught in US ‘049) would have led one of ordinary skill to modify the prior art reference (i.e. the aqueous pharmaceutical composition comprising a fusion protein having physiological activity comprising polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol as taught in US ‘043) to arrive at the claimed invention. There is a reasonable expectation of success as US ‘043 and US ‘049 teach compositions of antibodies or fusion proteins containing antibodies with the same excipients, known and used prior to the effective filing date of the application. Lyophilization is routine. In addition, both US ‘043 and US ‘049 are in analogous arts (i.e. compositions of antibodies or fusion proteins containing antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to lyophilize, as taught in US ‘049, the aqueous pharmaceutical composition comprising a fusion protein having physiological activity comprising polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol as taught in US ‘043.
Claim 39
US ‘049 further teaches the container for the lyophilized composition is borosilicate glass (¶ 0090, “freeze-drying process is applied to the solution in the vented container” and the container is “type I borosilicate glass”).
Claims 41-43
US ‘049 further teaches the lyophilized composition is stored for 36 months (¶ 0093, “a lyophilized or otherwise solid form of a protein is regarded as stable… [after storage for] about 36 months”) at temperatures ranging from about 4-8 °C (¶ 0095, “temperature at which the samples may be kept when assessing stability can be… about 4-8 °C).
US ‘049 further teaches the lyophilized composition contains up to 10% water, meeting the requirements for an aqueous solution as well (¶ 0013, “a pharmaceutically acceptable lyophilized cake comprising a stable protein, an excipient, and from about 0.5% to about 10% water”).
US ‘049 further teaches “[a] ‘stable’ protein undergoes little or no change in structure or specific activity after storage at room temperature for a prolonged period of time… which include reversible dimers and trimers” (¶ 0100). After storage, “100% of the native form of the protein can be detected” (¶ 0095), indicating 0% decomposition and 0% polymer by any form of measurement or calculation, including but not limited to the content ratio of the decomposition products and the polymer. Polymer is defined as multimers of the fusion protein as delineated in 112(b) section.
US ‘049 further teaches the borosilicate glass container is also amber glass (¶ 0090, “Exemplar vials may be made of clear glass or amber glass” and the glass being “type I borosilicate glass”).
US ‘049 does not teach the aqueous or lyophilized composition is stored in the dark. However, amber borosilicate glass is known to block light (Foxx Life Sciences, Title, “amber light-blocking round glass”; Pg. 1, ¶ 1, line 1, “borosilicate glass”).
Accordingly, claims 38-39 and 41-43 are rendered obvious over US ‘043 in view of US ‘049 as evidenced by Foxx Life Sciences.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-18, 21-33, 35, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34, 36-40, and 44-45 of U.S. Patent No. RE50240 (referred to as Pat. ‘240) in view of in view of EP 3589318 A1 (referred to as EP ‘318, published 2020-01-08) as evidenced by US 20190338043 A1 (referred to as US ‘043, filed 2017-12-26, published 2019-11-07).
Instant claims 1, 3, 5, 6, and 38
Instant claim 1 teaches an aqueous or lyophilized pharmaceutical composition comprising a protein having physiological activity and two different nonionic surfactants. Instant claims 3 and 5 teach the surfactants are polysorbate 80 as a polysorbate and polyoxyethylene(160) polyoxypropylene(30) glycol as a poloxamer. Instant claim 6 teaches the polysorbate has a concentration of 0.005-1.5 mg/mL and the poloxamer has a concentration of 0.05-0.6 mg/mL. Instant claim 38 teaches the aqueous composition is capable of being lyophilized.
Claims 1-34, 36-40, and 44-45 of Pat. ‘240 teach anti-human transferrin receptor Fab antibody and derivatives of said antibody, the physiological activity being binding human transferrin receptor.
Claims 1-34, 36-40, and 44-45 of Pat. ‘240 do not teach aqueous or lyophilized pharmaceutical composition nor two different nonionic surfactants.
EP ‘318 teaches “antibody formulation” (¶ 0001) comprising more than one nonionic surfactants (¶ 0095, “nonionic surfactants”; ¶ 0099, “formulations described herein can also include one or more additional excipients”) and that this formulation is important for improving antibody stability (¶ 0001, “providing improved colloidal stability in an antibody formulation”).
EP ‘318 further teaches the antibody formulation can be aqueous (¶ 00109, “liquid formulations”) or the aqueous composition can be lyophilized (¶ 0044, “formulation capable of being lyophilized”).
EP ‘318 further teaches different nonionic surfactant such as “polysorbate 80” (¶ 0030) and polyoxyethylene(160) polyoxypropylene(30) glycol (¶ 0095, “poloxamer 188”). Please note the specification of the instant application states, “Polyoxyethylene(160) polyoxypropylene(30) glycol is synonymous with poloxamer 188” (¶ 0075).
EP ‘318 further teaches the excipients in an antibody formulation have the following concentrations:
0.1 mg/mL polysorbate 80 (¶ 0097, the formulations described herein comprise a surfactant… about 0.01% [w/v]”; equivalent to 0.1 mg/mL as calculated below; claims 6-8 and 12-14),
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0.2 mg/mL polyoxyethylene(160) polyoxypropylene(30) glycol (¶ 0097, the formulations described herein comprise a surfactant… about 0.02% [w/v]”; equivalent to 0.2 mg/mL as calculated below; claims 6-8 and 12-14),
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Aqueous and lyophilized antibody formulations containing nonionic surfactants, specifically polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol, were known and used prior to the effective filing date of the application. In addition, both Pat. ‘240 and EP ‘318 are in analogous arts (i.e. antibodies). Since EP ‘318 teaches the aqueous or lyophilized antibody formulation is important for improving antibody stability, there is motivation for using this excipient.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. the aqueous and lyophilized antibody formulations containing nonionic surfactants, specifically polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol, are important for improving antibody stability as taught in EP ‘318) would have led one of ordinary skill to modify Pat. ‘240 (i.e. anti-human transferrin receptor antibody and derivatives of said antibody as taught in Pat. ‘240) to arrive at the claimed invention. There is a reasonable expectation of success as aqueous and lyophilized antibody formulations containing nonionic surfactants, specifically polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol, were known and used prior to the effective filing date of the application. In addition, both Pat. ‘240 and EP ‘318 are in analogous arts (i.e. antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application create an aqueous or lyophilized antibody formulation containing 0.1 mg/mL polysorbate 80 and 0.2 mg/mL polyoxyethylene(160) polyoxypropylene(30) glycol as taught in EP ‘318 wherein the antibody is an anti-human transferrin receptor antibody as taught in Pat. ‘240.
Instant claims 2 and 9-11
Instant claims 2 and 9-11 teach the aqueous or lyophilized pharmaceutical composition of instant claim 1 further comprises a neutral salt, a disaccharide, and a buffering agent (instant claim 2): the neutral salt being sodium chloride (instant claim 9), the disaccharide being sucrose (instant claim 10), and the buffering agent being citrate buffer (instant claim 11).
EP ‘318 further teaches the antibody formulation” (¶ 0001) comprises NaCl (¶ 0020, “invention thus further provides a formulation comprising… a salt”; ¶ 0022, “the salt is NaCl”), sucrose (¶ 0093, “The formulations described herein suitably comprise a sugar, for example, but not limited to…sucrose”), and citrate buffer (¶ 0087, “Exemplary buffers for use in the formulations provided herein include, but are not limited to… citrate”).
Instant claims 7-8 and 12-14
Instant claims 7-8 and 12-14 teach the pharmaceutical composition of instant claim 1 further comprises excipients at the following concentrations:
Polysorbate is 0.005-1.5 (instant claims 12), 0.025-1.0 (instant claim 7), 0.05-0.15 (instant claims 8 and 14), and 0.05-1.0 mg/mL (instant claim 13)
Poloxamer is 0.05-0.6 (instant claim 12), 0.1-0.5 (instant claim 7), 0.15-0.45 (instant claim 8), and 0.25-0.45 mg/mL (instant claims 13-14)
Neutral salt is 0.3-1.2 (instant claim 12), 0.5-1.0 (instant claim 13), and 0.7-0.9 mg/mL (instant claim 14)
Disaccharide is 50-100 (instant claim 12), 55-95 (instant claim 13), and 60-90 mg/mL (instant claim 14)
Buffering agent at is 10-30 (instant claim 12) and 15-25 mg/mL (instant claims 13-14)
EP ‘318 further teaches the excipients in an antibody formulation have the following concentrations:
0.1 mg/mL polysorbate 80 (¶ 0097, the formulations described herein comprise a surfactant… about 0.01% [w/v]”; equivalent to 0.1 mg/mL as calculated below; claims 7-8 and 12-14),
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0.2 mg/mL polyoxyethylene(160) polyoxypropylene(30) glycol (¶ 0097, the formulations described herein comprise a surfactant… about 0.02% [w/v]”; equivalent to 0.2 mg/mL as calculated below; claims 7-8 and 12-14),
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2.9-5.8 mg/mL to NaCl (¶ 0081, “The concentration of the ionic excipient, suitably salt, in the pharmaceutical formulations described herein is generally in the range of… about 50 mM to about 100 mM”; equivalent to about 2.9-5.8 mg/mL as calculated below),
National Center for Biotechnology Information states the molecular weight of NaCl is 58.44 g/mol (Pg. 1).
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80 mg/mL sucrose (¶ 0094, “the amount of sugar… in a formulation described herein is… about 8 % [w/v]”; equivalent to 80 mg/mL as calculated below; claims 12-14), and
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15 mM citrate buffer (¶ 0088, “The concentration of a buffer… in the pharmaceutical formulations described herein is generally… about 15 mM”; claims 12-14).
EP ‘318 teaches the antibody formulation comprising NaCl, sucrose, citrate buffer, polysorbate 80, and polyoxyethylene(160) polyoxypropylene(30) glycol for the purposes of “stabilizing the antibody” (¶ 0012, applicable to NaCl), “improv[ing] tonicity” (¶ 0024, applicable to sucrose), “maintaining the pH” (¶ 0087, applicable to citrate buffer), and “solubilizing” (¶ 0095, applicable to polysorbate 80 and polyoxyethylene[160] polyoxypropylene[30] glycol).
Regarding claims 12-14, EP ‘318 does not teach NaCl has a concentration of 0.3-1.2 mg/mL (claim 12), 0.5-1.0 mg/mL (claim 13), and 0.7-0.9 mg/mL (claim 14).
MPEP 2144.05(II)(A) states: "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. concentrations of NaCl, sucrose, citrate buffer, polysorbate 80, and polyoxyethylene[160] polyoxypropylene[30] glycol), so as to achieve optimal effect and maximal benefit (i.e. stabilize the antibody, improve tonicity, maintain pH, and solubilize as taught in EP ‘318). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of excipient concentrations would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed excipient concentrations to achieve them without undue experimentation in order to stabilize the antibody, improve tonicity, maintain pH, and solubilize as taught in EP ‘318.
Instant claims 15-16
Instant claims 15-16 teach the pharmaceutical composition of instant claim 1 has a pH of 4.5-6.5 (instant claim 15) and 5.0-6.0 (instant claim 16).
EP ’318 further teaches the pH is 6.0 (claim 12 of EP ’318).
Instant claim 17
Instant claim 17 teaches the pharmaceutical composition of instant claim 1 has a pH of 5.2-5.8.
EP ‘318 further teaches “[a]t more acidic pH, an increased rate of fragmentation, reduced conformational stability and increased aggregation can be observed. At more basic pH, the potential for increased oxidation, deamidation and fragmentation and incompatibility with glass containers are present” (¶ 0004). Therefore, pH is a result effective variable that can be optimized for antibody stability.
EP ‘318 does not teach the pH is 5.2-5.8.
MPEP 2144.05(II)(A) states: "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. pH), so as to achieve optimal effect and maximal benefit (i.e. stabilize the antibody as taught in EP ‘318). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of the pH would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed pHs to achieve them without undue experimentation in order to stabilize the antibody as taught in EP ‘318.
Instant claim 18, 27-28, and 33
Instant claims 18 teaches the pharmaceutical composition of instant claim 1, wherein the protein is a fusion protein of an antibody and a lysosomal enzyme. Instant claims 27-28 and 33 teach the antibody is anti-human transferrin receptor Fab antibody.
Claims 16-34, 36-40, and 44-45 of Pat. ‘240 teach a fusion protein of anti-human transferrin receptor Fab antibody and a lysosomal enzyme.
Instant claims 21-22
Instant claims 21-22 teach the fusion protein of instant claim 18 wherein lysosomal enzyme bonded at either the C-terminus or N-terminus of either the antibody light chain or heavy chain via a linker consisting of at least one amino acid.
Claims 17, 20-22, 24-29, 37-40, and 44-45 of Pat. ‘240 teach the fusion protein of anti-human transferrin receptor Fab antibody and a lysosomal enzyme, wherein the lysosomal enzyme bonded at either the C-terminus or N-terminus of either the antibody light chain or heavy chain via a linker consisting of at least one amino acid.
Instant claim 23
Instant claim 23 teach the fusion protein of instant claim 21, wherein the linker comprises an amino acid sequence selected from the group consisting of Gly-Ser, Gly-Gly-Ser, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and 2 to 10 of any of aforementioned amino acid sequences that are consecutively linked.
Claims 22, 24-29, 40, and 44-45 of Pat. ‘240 teach the linker of the fusion protein of anti-human transferrin receptor Fab antibody and a lysosomal enzyme is Gly-Ser or SEQ ID NO: 1 of the instant application. Claims 22, 24-25, and 40 of Pat. ‘240 use Gly-Ser. Claims 26-29 and 44-45 of Pat. ‘240 use SEQ ID NO: 1 of the instant application (recited as SEQ ID NO: 3 in Pat. ‘240).
Instant claims 24-26
Instant claims 24-26 teach the fusion protein of instant claim 18 wherein the lysosomal enzyme is a human lysosomal enzyme or human α-L-iduronidase.
Claims 18-19, 23-29, and 44-45 of Pat. ‘240 teach a fusion protein of anti-human transferrin receptor Fab antibody and a human lysosomal enzyme or human α-L-iduronidase.
Claims 29-32
Instant claims 29-32 teach the antibody of the fusion protein recognizes as antigen a molecule, specifically transferrin receptor, present on human cerebrovascular endothelial cells.
While claims 1-34, 36-40, and 44-45 of Pat. ‘240 teach anti-human transferrin receptor Fab antibody, Pat. ‘240 does not explicitly state the transferrin receptor is present on human cerebrovascular endothelial cells.
However, transferrin receptors are known to be is present on human cerebrovascular endothelial cells (US ‘043, ¶ 007, “Examples of those membrane proteins which occur on the endothelial cells of the brain capillaries include receptors for… transferrin”; ¶ 0247, “anti-hTfR [anti-human transferrin receptor] antibody”).
A person having ordinary skill in the art would recognize transferrin receptors are present on human cerebrovascular endothelial cells.
Claim 35
Instant claim 35 teaches the fusion protein of instant claim 28, wherein the antibody is anti-human transferrin receptor Fab antibody comprising SEQ ID NOs: 22 and 23, the lysosomal enzyme is human α-L-iduronidase comprising SEQ ID NO: 6, and the antibody and lysosomal enzyme are connected via SEQ ID NO: 4.
Claim 45 of Pat. ‘240 teaches a fusion protein of anti-human transferrin receptor Fab antibody and a lysosomal enzyme, wherein the antibody comprises SEQ ID NOs: 22 and 23 of the instant application (SEQ ID NOs: 23 and 61 respectively in Pat. ‘240), the lysosomal enzyme is human α-L-iduronidase comprising SEQ ID NO: 6 of the instant application (SEQ ID NO: 75 in Pat. ‘240), and the antibody and lysosomal enzyme are connected via SEQ ID NO: 4 (three consecutively linked amino acid sequences each set forth as SEQ ID NO: 3 of Pat. ‘240).
Claims 39 and 41-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34, 36-40, and 44-45 of U.S. Patent No. RE50240 (referred to as Pat. ‘240) in view of in view of US 20180099049 A1 (referred to as US ‘049, filed 2017-10-06, published 2018-04-12) as evidenced by Foxx Life Sciences (Borosil® Reusable Amber Light-Blocking Round Glass Media Storage Bottles with Easy to Open GL 45 Autoclavable PP Cap, Pouring Ring, and Enamel Marking Spot, 3L, 2/CS, 2026).
Instant claim 39
Instant claim 39 teaches a lyophilized pharmaceutical composition, obtained by lyophilizing an aqueous composition, comprising a protein having physiological activity, a polysorbate at 0.005-1.5 mg/mL, and a poloxamer at 0.05-0.6 mg/mL wherein the composition is encapsulated in a borosilicate glass container.
Claims 1-34, 36-40, and 44-45 of Pat. ‘240 teach anti-human transferrin receptor antibody and derivatives of said antibody, the physiological activity being binding human transferrin receptor.
Claims 1-34, 36-40, and 44-45 of Pat. ‘240 do not teach a pharmaceutical composition, a poloxamer, a polysorbate, nor a container.
US ‘049 teaches the inclusion of polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol in “pre-lyophilized protein-containing aqueous solution” (¶ 0067, polysorbate 80 and poloxamer 188 included as surfactants). Please note the specification of the instant application states, “Polyoxyethylene(160) polyoxypropylene(30) glycol is synonymous with poloxamer 188” (¶ 0075).
US ‘049 further teaches the surfactants polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol have a concentration of 0.1 mg/mL (¶ 0068, “0.01%” surfactant, equivalent to 0.1 mg/mL as calculated below).
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US ‘049 further teaches surfactants “provide additional stability by reducing protein-protein hydrophobic interaction” (¶ 0067).
US ‘049 further teaches the aqueous composition of a protein, specifically an antibody, is capable of being lyophilized (¶ 0027, “the pharmaceutically acceptable lyophilized cake is manufactured by combining a protein, a buffer, a nonionic surfactant, and one or more stabilizers in water to make a pre-lyophilized aqueous solution. The solution is then freeze-dried to make a cake… The freeze-dried [lyophilize] protein is in a ‘solid state’”; ¶ 0023, “the protein is a therapeutic antibody”).
US ‘049 further teaches the container for the lyophilized composition is borosilicate glass (¶ 0090, “freeze-drying process is applied to the solution in the vented container” and the container is “type I borosilicate glass”).
US ‘049 further teaches “[l]yophilization (freeze drying under controlled conditions) is commonly used for long-term storage of proteins” (¶ 0003).
Lyophilization in a borosilicate glass container of an aqueous composition containing antibodies and surfactants was known and used prior to the effective filing date of the application. In addition, both Pat. ‘240 and US ‘049 are in analogous arts (i.e. antibodies). Since US ‘049 teaches lyophilization in a borosilicate glass container and the inclusion of surfactants is useful for long-term storage and stability of proteins, there is motivation for lyophilization in a borosilicate glass container of an aqueous composition containing the antibodies of Pat. ‘240 and surfactants.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. lyophilization in a borosilicate glass container and the inclusion of surfactants is useful for long-term storage and stability of proteins as taught in US ‘049) would have led one of ordinary skill to modify the prior art reference (i.e. anti-human transferrin receptor antibody and derivatives of said antibody as taught in Pat. ‘240) to arrive at the claimed invention. There is a reasonable expectation of success as Pat. ‘240 and US ‘049 teach antibodies and compositions of antibodies respectively, known and used prior to the effective filing date of the application; it is routine to optimize a composition for storage. In addition, both Pat. ‘240 and US ‘049 are in analogous arts (i.e. antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to create a lyophilized pharmaceutical composition, obtained by lyophilizing an aqueous composition in a borosilicate glass container, comprising an antibody and the nonionic surfactants polysorbate 80 and polyoxyethylene(160) polyoxypropylene(30) glycol with a concentration of 0.1 mg/mL as taught in US ‘049 using the anti-human transferrin receptor antibody and derivatives of said antibody as taught in Pat. ‘240.
Claims 41-43
US ‘049 further teaches the lyophilized composition is stored for 36 months (¶ 0093, “a lyophilized or otherwise solid form of a protein is regarded as stable… [after storage for] about 36 months”) at temperatures ranging from about 4-8 °C (¶ 0095, “temperature at which the samples may be kept when assessing stability can be… about 4-8 °C).
US ‘049 further teaches the lyophilized composition contains up to 10% water, meeting the requirements for an aqueous solution as well (¶ 0013, “a pharmaceutically acceptable lyophilized cake comprising a stable protein, an excipient, and from about 0.5% to about 10% water”).
US ‘049 further teaches “[a] ‘stable’ protein undergoes little or no change in structure or specific activity after storage at room temperature for a prolonged period of time… which include reversible dimers and trimers” (¶ 0100). After storage, “100% of the native form of the protein can be detected” (¶ 0095), indicating 0% decomposition and 0% polymer by any form of measurement or calculation, including but not limited to the content ratio of the decomposition products and the polymer. Polymer is defined as multimers of the fusion protein as delineated in 112(b) section.
US ‘049 further teaches the borosilicate glass container is also amber glass (¶ 0090, “Exemplar vials may be made of clear glass or amber glass” and the glass being “type I borosilicate glass”).
US ‘049 does not teach the aqueous or lyophilized composition is stored in the dark. However, amber borosilicate glass is known to block light (Foxx Life Sciences, Title, “amber light-blocking round glass”; Pg. 1, ¶ 1, line 1, “borosilicate glass”).
Claims 1-3, 5-18, 21-33, 35, 38-39, and 41-43, or a subset of said claims as indicated in the table below, are rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the reference U.S. Patent Nos. in the table below in view of EP 3589318 A1 (referred to as EP ‘318, published 2020-01-08) and US 20180099049 A1 (referred to as US ‘049, filed 2017-10-06, published 2018-04-12) as evidenced US 20190338043 A1 (referred to as US ‘043, filed 2017-12-26, published 2019-11-07) and Foxx Life Sciences (Borosil® Reusable Amber Light-Blocking Round Glass Media Storage Bottles with Easy to Open GL 45 Autoclavable PP Cap, Pouring Ring, and Enamel Marking Spot, 3L, 2/CS, 2026).
It is noted that the reference patents summarized in the table below are directed to anti-human transferrin receptor antibodies and fusions of said antibodies with lysosomal enzymes, encompassing proteins recited in the instant claims. Even if the antibodies and fusions thereof recited in the reference patents differ from the instant invention, the inventions are analogous to EP ‘318 and US ‘049, which concern antibody compositions. The rejections as described in numbers 1-2 in the double patenting section apply.
Patent Number
Brief Description of Invention
Pertinent claims
Instant Claims
11111308
Anti-human transferrin receptor antibody and fusions of said antibody with lysosomal enzyme
1-26, 28-36, 39-42
1-3, 5-18, 21-33, 35, 38-39, and 41-43
12145995
Pharmaceutical agent comprising anti-human transferrin receptor antibody and fusion of said antibody with lysosomal enzyme
1-38
1-3, 5-18, 21-33, 35, 38-39, and 41-43
11248045
Anti-human transferrin receptor antibody and fusions of said antibody with lysosomal enzyme
1
1-3, 5-18, 24-25, 27, 29-32, 38-39, and 41-43
9994641
Anti-human transferrin receptor antibody and fusions of said antibody with lysosomal enzyme
1, 3-6
1-3, 5-18, 24-25, 27, 29-32, 38-39, and 41-43
10940185
Formulation of anti-human transferrin receptor antibody fused with lysosomal enzyme
1-28
1-3, 5-18, 21-27, 29, 30-32, 38-39, and 41-43
10759864
Anti-human transferrin receptor antibody and fusions of said antibody with lysosomal enzyme
1-7, 10-34, 36-40
1-3, 5-18, 21-33, 38-39, and 41-43
11932699
Composition of anti-human transferrin receptor antibody fused with lysosomal enzyme
1
1-3, 5-18, 24-25, 27, 29-32, 38-39, and 41-43
Conclusion
Claims 1-35, 38-39, and 41-43 are pending. Claims 4, 19-20, and 34 are withdrawn from further consideration. Claims 1-3, 5-18, 21-33, 35, 38-39, and 41-43 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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