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 .
Election/Restrictions
Applicant’s election without traverse of the species: substitutions between glycine and alanine (claim 103), vascular dysfunction (claim 112), and parenteral administration (claim 118) in the reply filed on 03/26/2026 is acknowledged.
Priority
The instant application filed on 08/04/2023 is a 371 of PCT/EP2016/072066 filed on 09/18/2016, which claims priority to CON 15/760,641 filed on 03/16/2018, which claims priority to GB1516516.0 filed on 09/17/2015. GB1516516.0 finds support for the instantly claimed invention; therefore, the effective filing date of the instant application is 09/17/2015.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/04/2023, 04/10/2024, 10/17/2024, and 12/18/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 79 is objected to because of the following informalities: the abbreviation “AnxA5” should be completely spelled out upon first use. Appropriate correction is required. This is an objection, not a rejection, because AnxA5 is spelled out in the instant specification to be “Annexin A5” (see, e.g., instant specification, pg. 1, line 14).
Claim 79 is objected to because of the following informalities: “the composition comprises non-ionic surfactant” should instead read “the composition comprises a non-ionic surfactant”. Appropriate correction is required. This is an objection, not a rejection, because this appears to be a typographical error.
Claim 96 is objected to because of the following informalities: the abbreviation “RGD” should be completely spelled out upon first use. Appropriate correction is required. This is an objection, not a rejection, because RGD is spelled out in the instant specification to be “arginine-glycine-aspartate”.
Claim 115 is objected to because of the following informalities: “…reducing the rate of, the transmission of a viral infection” should instead read “…reducing the rate of transmission of a viral infection”. Appropriate correction is required. This is an objection, not a rejection, because this appears to be a typographical error.
Claim Rejections - 35 USC § 112(b), Indefiniteness
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 79-122 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 79 and 107-109 recite the abbreviation “EU”; however, this abbreviation is not defined in the instant specification and abbreviations must be completely spelled out upon first use in the claims. Moreover, “EU” can stand for multiple abbreviations; therefore, it is unclear what “EU” is abbreviating. For the purposes of applying prior art, the Examiner has interpreted “EU” to be “Endotoxin Units”.
Claim 79 recites “…the composition comprises an endotoxin content that is at a detectable level, and wherein the detectable level is less than 20 EU per mg AnxA5…” and “…the composition comprises host cell nucleic acid of an endotoxin-producing host cell with a cell wall at a detectable level, wherein the detectable level is less than 500 pg per mg of AnxA5 protein…”; however, “less than 20 EU per mg AnxA5” includes 0 EU per mg AnxA5 and “less than 500 pg per mg of AnxA5 protein” includes 0 pg per mg of AnxA5 protein; therefore, it is unclear how the endotoxin content and nucleic acid content can be detectable when the detectable level can comprise an endotoxin content of 0 EU per mg AnxA5 and a nucleic acid content of 0 pg per mg AnxA5 protein, respectively, which is undetectable. For the purposes of applying prior art, the Examiner has interpreted this to mean that there is a detectable level of endotoxin that is less than 20 EU per mg AnxA5, but not 0 EU per mg AnxA5. Additionally, the Examiner has interpreted this to mean that there is a detectable level of host cell nucleic acid that is less than 500 pg per mg of AnxA5, but not 0 pg per mg of AnxA5.
Claims 81 and 101 recites “(SEQ ID NO:1)” in parentheses; however, it is unclear if the SEQ ID NO recited in parentheses is part of the claimed invention, or a preferred embodiment. For the purposes of applying prior art, the Examiner has interpreted SEQ ID NO:1 recited in parentheses to be a preferred embodiment and not part of the claimed invention.
Claim 84 recites “at least about”; however it is unclear if the concentration of AnxA5 protein is at least 1 mg/mL, which would include concentrations at and above 1 mg/mL, or if the concentration of AnxA5 protein is about 1 mg/mL, which would include concentrations below and above 1 mg/mL.
Claim 87 recites “…wherein the composition comprises NaCl at a concentration that maintains AnxA5 protein in a form that is predominately monomeric”; however, it is unclear what “predominately monomeric” means. The instant specification does not define what “predominately monomeric” means; therefore, for the purposes of applying prior art, the Examiner has interpreted “predominately monomeric” to mean that greater than 50% of the AnxA5 is in monomeric form.
Claims 88 and 93 recite “…non-AnxA5 protein at a level less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5 ng per mg of AnxA5 protein”; however, it is unclear if all non-AnxA5 protein levels are being claimed, or if one protein level is being claimed because there is no and/or linking phrase between 10 and 5 ng. Furthermore, non-AnxA5 protein at a level less than 5 ng would include 0 ng; therefore, it is unclear how the composition can comprise non-AnxA5 protein when the level of non-AnxA5 protein can comprise 0 ng. For the purposes of Applying prior art, the Examiner has interpreted that the non-AnxA5 protein level can be less than 5 ng per mg AnxA5 protein, but not 0 ng per mg AnxA5 protein. Moreover, for the purposes of applying prior art, the Examiner has interpreted the composition to have a non-AnxA5 protein level of 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 ng per mg of AnxA5 protein; therefore, only one protein level is contained within the composition.
Claims 107-109 recite “…wherein the detectable level of endotoxin in less than 10 EU per mg AnxA5”, “…wherein the detectable level of endotoxin in less than 5 EU per mg AnxA5”, and “…wherein the detectable level of endotoxin in less than 1 EU per mg AnxA5”, respectively; however, similar to the 112(b) rejection for claim 79 above, it is unclear how there can be a detectable level of endotoxin when the level of endotoxin can be less than 1-10 EU, which can include 0 EU per mg AnxA5. For the purposes of applying prior art, the Examiner has interpreted this to mean that that the detectable level of endotoxin is less than 1-10 EU per mg AnxA5, but not 0 EU per mg AnxA5.
Claim 111 recites “…wherein the detectable level of host cell nucleic acid of an endotoxin-producing host cell with a cell wall is less than 10 pg per mg of AnxA5 protein”; however, similar to the 112(b) rejection above for claim 79, it is unclear how there can be a detectable level of host cell nucleic acid when the level is less than 10 pg per mg of AnxA5 protein, which can include 0 pg per mg of AnxA5 protein. For the purposes of applying prior art, the Examiner has interpreted this to mean that the level of host cell nucleic acid is less than 10 pg per mg of AnxA5 protein, but not 0 pg per mg of AnxA5 protein.
Claim 115 recites a method of treating transmission of a viral invention; however, it is unclear how one would treat transmission of a viral infection since transmission of an infection is not something to be treated, but instead something to be prevented or reducing the rate of.
Claim 122 recites “…wherein the unit dosage form contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg of the AnxA5 protein”; however, it is unclear if all dosages are required or if one dosage is required in the unit dosage form because there is no and/or linking phrase between 9 and 10 mg. For the purposes of applying prior art, the Examiner has interpreted this to mean that the unit dosage form contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of the AnxA5 protein; therefore, only one concentration of AnxA5 is contained within the unit dosage form.
).
Claim Rejections - 35 USC § 112(a), Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 79-122 are rejected under 35 U.S.C. 112(a) 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.
Independent claim 79 recites “…an endotoxin-producing host cell…”. Claim 80 recites “…a condition characterised by phosphatidylserine exposed on the biological membrane of pathological cells…”. Claim 87 recites “…wherein the composition comprises NaCl at a concentration that maintains AnxA5 protein in a form that is predominately monomeric.” Claim 100 recites “…wherein the AnxA5 protein is a fusion protein comprising an AnxA5 protein and a fusion partner.” Claim 112 recites “…a method of treating, preventing, or reducing the risk of vascular dysfunction”. Claim 113 recites “…a method of treating, preventing, or reducing the risk of developing retinal vein occlusion.” Claim 114 recites “…a method of treating, preventing, or reducing the risk of developing a cardiovascular disease.” Claim 115 recites “…a method of treating, preventing, or reducing the rate of, the transmission of a viral infection.” Claim 116 recites “…a method of treating, preventing, or reducing the risk of vascular dysfunction.” Claim 117 recites “…a method of treating, preventing, or reducing the risk of haematological disorders.” Therefore, Applicant is broadly claiming endotoxin-producing host cells; conditions characterized by phosphatidylserine exposed on biological membranes; concentrations of NaCl that maintain AnxA5 in monomeric form; and AnxA5 fusion proteins; however, the instant specification does not describe these genera in enough specificity such that the Applicant has shown possession of the entire genus, by setting forth a representative number of species, for each claim recited above. Furthermore, Applicant is claiming treatment, prevention, or reduction in the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders; put Applicant has not shown possession of treatment, prevention, or reduction in any of these diseases or disorders, in general, nor has Applicant set forth a representative number of species for each claimed disease or disorder.
Regarding the endotoxin-producing host cell recited in claim 79, this host cell is described functionally (i.e., by what it does instead of what it is). The instant specification states “At least in the context of the first aspect of the present invention, and optionally in the context of all aspects of the present invention, the host cell is an endotoxin-producing host cell with a cell wall, and thus is typically a gram-negative bacteria, such as E. coli, for example, the E. coli strains DH5 available from Bethesda Research Laboratories Inc., Bethesda, MD, USA, and RR1 available from the American Type Culture Collection” (see, e.g., instant specification, pg. 17, lines 11-16). Therefore, the instant specification teaches E. coli as the endotoxin-producing host cell, but also states that theoretically the endotoxin-producing host cell strain can be any gram-negative bacterium. Furthermore, Examples 1 and 3 of the instant specification teaches that AnxA5 is expressed in E. coli (see, e.g., instant specification, pgs. 78 and 100). Therefore, based on the teachings in the instant specification, Applicant has not provided a representative number of species for the claimed “endotoxin-producing host cell” genus, as endotoxin-producing bacteria includes all gram-negative bacteria (see, e.g., Galanos, “Bacterial endotoxins: biological properties and mechanisms of action”). Therefore, Applicant has only described and reduced to practice E. coli, which is one gram-negative bacteria that produces endotoxin; however, Applicant does not provide a representative number of species for the claimed genus because all gram negative bacteria produce endotoxins and description of one gram negative bacterium (i.e., E. coli) is not representative of the entire genus (i.e., endotoxin-producing host cells).
Regarding the condition characterised by phosphatidylserine exposed on the biological membrane of pathological cells as recited in claim 80, this condition is described functionally (i.e., by what is does instead of what is is). The instant specification states phosphatidylserine is exposed on apoptotic cells (see, e.g., instant specification, pg. 16). Moreover, the instant specification describes multiple diseases that can be treated via administration of recombinant AnxA5, such as, for example, atherothrombosis, vascular dysfunction, restenosis (see, e.g., instant specification, pgs. 2 and 55), vasculitides (see, e.g., instant specification, pg. 55), and TIM-1 associated diseases and disorders (see, e.g., instant specification, pgs. 69-74); however, the instant specification does not teach that these diseases have phosphatidylserine exposure. Furthermore, Zwaal (Surface exposure of phosphatidylserine in pathological cells; 2005) teaches Scott syndrome, antiphospholipid syndrome, sickle cell anemia, thalassemia, stomatocytosis, uremia, kidney stone disease, diabetes and hyperglycemia, viral and bacterial infections, pre-eclampsia, hyperbilirubinemia, neoplasia, cystic fibrosis and bronchiectasis, and PS receptor deficiency as diseases or disorders associated with abnormal phosphatidylserine exposure on cells (see, e.g., Zwaal, pgs. 975-982). Therefore, based on the teachings in the instant specification, Applicant has not provided a representative number of species for the claimed “condition characterised by phosphatidylserine exposure on the biological membrane of pathological cells” because there are many diseases and disorders that have phosphatidylserine exposure, as evidence by the teachings of Zwaal, and Applicant only teaches apoptotic cells as cells with phosphatidylserine exposure. Description of one condition characterized by phosphatidylserine exposure on pathological cells is not sufficient and does not provide a representative number of species for the claimed genus.
Regarding the NaCl concentration for maintaining AnxA5 in predominately monomeric form as recited in claim 87, this concentration of NaCl is described functionally (i.e., by what it does instead of what it is). The instant specification states that “NaCl can be useful to maintain the AnxA5 product in a monomeric form during storage. Accordingly, the processes of the present invention may provide a final sterile AnxA5 protein product, wherein the NaCl concentration present maintains AnxA5 protein in a form that is predominantly (that is, greater than about 50%, such as 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or substantially 100%) monomeric” (see, e.g., instant specification, pg. 48). The instant specification states that the final sterile AnxA5 composition can comprise “150 mM NaCl (e.g.
±
50, 40, 30, 20 or 10 mM), but Applicant does not provide written description, support, and/or guidance that these NaCl concentrations maintain the AnxA5 protein in a predominately monomeric form. Therefore, based on this, the instant specification lacks written description, guidance, and concentrations pertaining to the concentration of NaCl that results in AnxA5 being in a predominately monomeric form.
Regarding the fusion protein comprising an AnxA5 protein and fusion partner as recited in claim 100, the instant specification states “In a further embodiment, the AnxA5 protein that is purified and/or recovered may be a fusion protein, which fusion protein comprises, consists essentially of, or consists of: (a) one or more protein sequences comprising the sequence of fusion partner that is/are fused to; (b) one or more protein sequences that comprises, consists essentially of, or consists of, a protein having the sequence of human Annexin A5 (SEQ ID NO:1, as shown in Fig 1), either with or without the N-terminal methionine, or a variant or mutant thereof, or dimer as described above” (see, e.g., instant specification, pg. 12). The instant specification also teaches examples of how the amino acid sequences can be arranged within the fusion protein (see, e.g., instant specification, pgs. 12-13). Additionally, the instant specification states “For example the fusion partner polypeptide sequence(s) may be suitable to extend the half-life of the molecule within a patient's circulatory system and/or add further functionality to the molecule, such as to add additional therapeutic properties (e.g. anti-coagulant, cell inhibition and/or killing, etc.)” (see, e.g., instant specification, pg. 13). However, the instant specification does not provide an actual reduction to practice, or sequence examples, or actual fusion partners with AnxA5 that show that the Applicant has possession of an AnxA5 fusion protein. Applicant only provides embodiments of how the fusion partners and amino acids can be arranged within the fusion protein, but does not actually provide written description, guidance, or sequences showing that Applicant is in possession of AnxA5 fusion protein(s).
Regarding the treatment, prevention, or risk reduction of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infection, and haematological disorders as recited in claims 112-117, Applicant does not provide written description or guidance on the treatment, prevention or risk reduction of any of these claimed diseases. The instant specification provides embodiments of various diseases that AnxA5 may be administered to treat; however, Applicant does not provide support by means of examples, or a reduction to practice that the claimed AnxA5 composition actually does treat, prevent or reduce the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infection, and haematological disorders. Furthermore, Applicant does not teach methods of administering AnxA5 to treat, prevent, or reduce the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infection, and haematological disorders. Applicant is merely providing a result that one might achieve if one made that invention and the specification merely outlines goals that the Applicant hopes the claimed invention achieves and the problems the invention will hopefully ameliorate, which does not satisfy the written description requirement. Therefore, the instant specification does not provide written description, guidance, methods, or a reduction to practice that AnxA5 can actually treat, prevent, or reduce the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infection, and haematological disorders. Furthermore, Applicant does not set forth a representative number of species for the claimed genus for each claimed disease or disorder. For example, Applicant claims treating, preventing or reducing the rate of transmission of a viral infection; however, there are hundreds of viruses that encompass viral infections, and Applicant has not set forth an “actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above) (see, e.g., MPEP 2163(II)(3)(a)(ii)). Furthermore, based on this, Applicant has not shown possession of any claimed genus of disease or disorder because Applicant has not set forth a representative number of species .
Claim Rejections - 35 USC § 112(a), Scope of Enablement
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.
Claims 79-122 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for administration of AnxA5 for treatment of certain diseases, does not reasonably provide enablement for administration of recombinant AnxA5 in combination with a non-ionic surfactant, endotoxin from host cell, and host cell nucleic acid for the treatment of the claimed diseases and/or disorders in any population of human or animal. 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.
In re Wands (858 F2d, 721, 727, 8 USPQ 2d 1400, 1404 (Fed Cir. 1988)), the issue of enablement in molecular biology was considered. It was held that the following factors should be
considered to determine whether the claimed invention would require the skilled artisan undue
experimentation:
1) Amount of experimentation necessary;
2) Amount of direction or guidance presented;
3) Presence or absence of working examples;
4) Nature of the invention;
5) State of the prior art;
6) Relative skill of those in the art;
7) Predictability or unpredictability of the art; and
8) Breadth of the claims.
Nature of the Invention:
The invention is directed towards a method of treating, preventing, or reducing the risk of a disease, infection, and disorder in a human or animal in need thereof through administration of a sterile, recombinant AnxA5 composition that comprises a non-ionic surfactant, wherein the composition comprises an endotoxin content and a host cell nucleic acid content.
Breadth of the claims:
Regarding independent claim 79, the method of treating a human or animal in need thereof comprises administering a composition that comprises host cell nucleic acid from an endotoxin-producing host cell, which can be any and all endotoxin-producing host cells. Additionally, the claim does not recite a specific population; therefore, Applicant is attempting to treat all populations.
Regarding dependent claim 80, the method of treating a condition comprises treating all conditions characterized by phosphatidylserine exposed on the biological membrane of pathological cells.
Regarding dependent claims 112 and 116, the method of treating, preventing, or reducing the risk of vascular dysfunction through administration of the AnxA5 composition comprises treating, preventing, or reducing the risk of all types/forms of vascular dysfunction.
Regarding dependent claim 113, administration of recombinant AnxA5 results in treating, preventing, or reducing the risk of retinal vein occlusion.
Regarding dependent claim 114, the method of treating, preventing, or reducing the risk of cardiovascular disease through administration of the AnxA5 composition comprises treating, preventing, or reducing all types/forms of cardiovascular disease.
Regarding dependent claim 115, the method of treating, preventing, or reducing the rate of viral transmission through administration of the AnxA5 composition comprises treating, preventing, or reducing the rate of all viruses.
Regarding dependent claim 117, the method of treating, preventing, or reducing the risk of haematological disorders through administration of the AnxA5 composition comprises treating, preventing, or reducing all types/forms of haematological disorders.
Amount of direction or guidance presented:
Regarding independent claim 79 pertaining to the endotoxin-producing host cell, the instant specification teaches “A particular challenge, when recombinantly expressing Annexin A5 in standard bacterial host cells such as E. coli, is contamination with host cell derived components, and in particular with endotoxin. Endotoxin is a lipopolysaccharide (LPS), which is formed of a lipid and a polysaccharide composed of O-antigen, outer core and inner core joined by a covalent bond; LPS is found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals” (see, e.g., instant specification, pg. 2, lines 31-36). Furthermore, the instant specification states “At least in the context of the first aspect of the present invention, and optionally in the context of all aspects of the present invention, the host cell is an endotoxin-producing host cell with a cell wall, and thus is typically a gram-negative bacteria, such as E. coli, for example, the E. coli strains DH5 available from Bethesda Research Laboratories Inc., Bethesda, MD, USA, and RR1 available from the American Type Culture Collection” (see, e.g., instant specification, pg. 17, lines 11-16). Therefore, the instant specification teaches E. coli as the endotoxin-producing host cell, but also states that theoretically the endotoxin-producing host cell strain can be any gram-negative bacterium.
Regarding claim 80 pertaining to treating conditions characterized by phosphatidylserine exposed on the biological membrane of pathological cells, the instant specification teaches that viruses, particularly enveloped viruses, comprise phosphatidylserine in their envelope (see, e.g., instant specification, pg. 66, lines 34-36). Additionally, the instant specification teaches that phosphatidylserine is exposed on apoptotic cells (see, e.g., instant specification, pg. 16, lines 9-10). Therefore, the instant specification teaches that the conditions characterized by exposure of phosphatidylserine on the biological membrane of pathological cells can be infection by any enveloped virus, or apoptosis of cells, in general.
Regarding claims 112-117 pertaining to treating, preventing, or reducing the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders, the instant specification states that the AnxA5 composition can be used to treat, prevent, or reduce the risk of a myriad of diseases, those of which include vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders (see, e.g., instant specification, pgs. 55-74).
Presence or absence of working examples:
Regarding claim 79 pertaining to the endotoxin-producing host cell, the Examples 1-4 teach that the endotoxin-producing host cell used to recombinantly produce AnxA5 is E. coli -(see, e.g., instant specification, Examples 1-4, pgs. 77-102). Therefore, Applicant only provides working examples in the instant specification for E. coli as the endotoxin-producing host cell, and there is no extrapolation in the instant specification for how other endotoxin-producing bacterial strains can express human recombinant AnxA5 for administration for treatment, prevention, and reduction in the risk of various diseases. Based on this, Applicant would not be enabled for all endotoxin-producing host cells, and would only be enabled for E. coli.
Regarding claim 80 pertaining to treating conditions characterized by phosphatidylserine exposed on the biological membrane of pathological cells, the instant specification does not provide working examples for treating conditions characterized by phosphatidylserine exposed on the biological membrane of pathological cells. Based on this, Applicant would not be enabled for treating conditions characterized by phosphatidylserine exposed on the biological membrane of pathological cells.
Regarding claims 112-117 pertaining to treating, preventing, or reducing the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders, the instant specification does not provide working examples for treating, preventing, or reducing the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders. Based on this, Applicant would not be enabled for treating, preventing, or reducing the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders.
State of the prior art:
Regarding claim 79 pertaining to the endotoxin-producing host cell, the prior art teaches that AnxA5 is recombinantly produced in E. coli (see, e.g., US2006/0009381, [0090]; US2006/0228299, [0282]; WO2010/043045, pg. 21, lines 17-20), which is a gram negative endotoxin producing bacterial cell. Furthermore, Galanos teaches that endotoxin-producing bacteria includes all gram-negative bacteria (see, e.g., Galanos, “Bacterial endotoxins: biological properties and mechanisms of action”) and there are many different types of gram negative bacteria, and probably even unidentified gram negative bacteria.
Regarding claim 80 pertaining to treating conditions characterized by phosphatidylserine exposed on the biological membrane of pathological cells, Zwaal (Surface exposure of phosphatidylserine in pathological cells; 2005) teaches Scott syndrome, antiphospholipid syndrome, sickle cell anemia, thalassemia, stomatocytosis, uremia, kidney stone disease, diabetes and hyperglycemia, viral and bacterial infections, pre-eclampsia, hyperbilirubinemia, neoplasia, cystic fibrosis and bronchiectasis, and PS receptor deficiency as diseases or disorders associated with abnormal phosphatidylserine exposure on cells (see, e.g., Zwaal, pgs. 975-982). However, the prior art does not teach treatment of all of these diseases via administration of a composition comprising recombinant AnxA5 that is produced in endotoxin-producing host cells, wherein the composition further comprises a non-ionic surfactant, host cell endotoxin content, and host cell nucleic acid content.
Regarding claims 112-117 pertaining to treating, preventing, or reducing the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders, Cederholm teaches that AnxA5 can be used to treat atherothrombosis and plaque rupture, which is the main cause of cardiovascular disease (see, e.g., WO2005/099744, pg. 16, lines 13-15). Frostegar teaches that AnxA5 “can restore normal endothelium mediated vasodilatation in atherosclerotic mice, by a NO dependent mechanism. Thus, Annexin A5 or analogues thereof provide a new treatment modality with anti-ischaemic effects that can normalise vasomotion abnormalities in diseases where this abnormality is due to a hampered eNOS function or NO bioavailability” (see, e.g., US2009/077764, pg. 5, lines 22-26). Pettersson teaches that “the anti-inflammatory effects of annexin A5 in this model of inflammation driven vascular disease. Inflammation (measured as accumulation of leucocytes in the vessel wall) was markedly inhibited by annexin A5 treatment. Furthermore, annexin A5 could also significantly reduce the number of inflammatory cells that were activated, as fewer cells were staining positive for the pro- inflammatory cytokine MCP-1” (see, e.g., WO2009/103977; Example 3). Pryzdial teaches that AnxA5 can inhibit viral replication and infection for cytomegalovirus (see, e.g., US2006/0057591, [0058]). However, overall, the prior art does not teach the administration of a composition comprising recombinant AnxA5, a non-ionic surfactant, endotoxin from host cell, and host cell nucleic acid for the treatment of these diseases and/or disorders. Instead, the prior art focuses on compositions simply containing AnxA5. Additionally, the prior art mainly focuses on treatment of diseases and/or disorders with AnxA5 instead of focusing on prevention and risk reduction. For example, prevention of viral infection can occur by “(1) eliminating nonhuman reservoirs, (2) eliminating the vector, and (3) improving sanitation” (see, e.g., Goldenthal, “Control of Viral Infections and Diseases”); however, prevention is not centered around parentally administering a pharmaceutical therapeutic to an individual before they have an infection. Along these lines, the prior art does not teach prevention of viral infections, and prevention of any of the claimed diseases or disorders, in general, by preemptively administering parentally a therapeutic that comprises AnxA5, a non-ionic surfactant, host cell nucleic acid, and endotoxin.
Relative skill of those in the art:
Based on the state of the prior art, the relative skill of those in the art pertaining to administration of a composition comprising recombinant AnxA5, a non-ionic surfactant, endotoxin content, and host cell nucleic acid content, wherein the composition is administered to treat, prevent, or reduce the risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders is low.
Predictability or unpredictability of the art:
The level of unpredictability within the art is high, as there are many types of endotoxin-producing host cell strains that can be engineered to recombinant express human AnxA5; however, it is unpredictable as to whether or not these host cells are capable of either actually expressing and producing AnxA5, and if the expressed AnxA5 protein will actually result in the treatment, prevention, or reduction in risk of vascular dysfunction, retinal vein occlusion, cardiovascular disease, viral infections, and haematological disorders. Moreover, there are many diseases and conditions that are encompassed by phosphatidylserine exposure on the biological membrane of a pathological cell or virus; therefore, it is unpredictable as to whether AnxA5 in a composition with a non-ionic surfactant, host cell proteins, and host cell nucleic acids will actually treat or prevent these diseases. Furthermore, it is unpredictable how compositions comprising the recombinant AnxA5 produced in a wide range of host cells would interact in a composition with a non-ionic surfactant. Moreover, it unpredictable how host cell nucleic acid(s) and host cell endotoxins would interact with the AnxA5 and non-ionic surfactant in the composition, and if the interaction between these components would affect the efficacy of the composition against the different diseases and/or disorders.
Amount of experimentation necessary:
Since the prior art mainly focuses on the treatment of diseases and/or disorders with AnxA5, the amount of experimentation for prevention and risk reduction is high for diseases and/or disorders. Furthermore, the prior art focuses on expression of AnxA5 in E. coli and no other endotoxin-producing host cells; therefore, amount of experimentation for determining if AnxA5 can be efficiency produced in other endotoxin producing host cells is high. Moreover, the prior art does not teach compositions comprising AnxA5, a non-ionic surfactant, host cell nucleic acids, and host cell endotoxins; therefore, the amount of experimentation necessary to determine if these components interact to increase or decrease efficacy of this composition for the treatment, prevention, and/or risk reduction for different diseases and/or disorders is high. Furthermore, the amount of experimentation necessary to determine if AnxA5 maintains efficacy against diseases and/or disorders when produced in other endotoxin producing host cells besides E. coli is high, as there are many gram negative bacteria that can be used to express AnxA5 and there are many diseases and/or disorders that can be treated.
Claim Rejections - 35 USC § 103, Obviousness
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 79-80, 82-84, 95-97, 100-101, 104-118, and 121 are rejected under 35 U.S.C. 103 as being unpatentable over Reutelingsperger (US 2006/0009381; Date of Publication: January 12, 2006 – cited in the IDS filed on 08/04/2023) in view of Kerwin (Polysorbates 20 and 80 Use in the Formulation of Protein Biotherapeutics: Structure and Degradation Pathways; 2008 – cited in the IDS filed on 08/04/2023), Park (Annexin A5 Increases Survival in Murine Sepsis Model by Inhibiting HMGB1-Mediated Proinflammation and Coagulation; 2016 – cited in the IDS filed on 08/04/2023), Petsch (Endotoxin removal from protein solutions; 2000), and Takeda (U.S. Patent No. 8,420,789; Date of Publication: April 16, 2013).
Reutelingsperger’s general disclosure relates to methods and compositions for the treatment, diagnosis, and prevention of diseases, such as neoplastic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases, wherein method comprises administration of pharmaceutical complexes comprising annexins coupled to pharmaceutical compounds or carrier to subjects (see, e.g., Reutelingsperger, abstract).
Regarding claim 79 pertaining to treating a human or animal in need thereof with a sterile AnxA5 composition, Reutelingsperger teaches “methods and compositions for the treatment, diagnosis, prevention, and research of diseases, such as neoplastic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases. The methods include the administration to subjects of pharmaceutical complexes comprising annexins and annexin variants coupled to pharmaceutical compounds or carriers” (see, e.g., Reutelingsperger, [0025]). Reutelingsperger teaches “The methods include administering a composition comprising an effective amount of complex comprising at least one compound and an annexin or annexin variant (see, e.g., Reutelingsperger, [0070]). Moreover, Reutelingsperger teaches that the annexin is Annexin A5 (see, e.g., Reutelingsperger, [0037]). Additionally, Reutelingsperger teaches “The preparation preferably will be sterile, especially if it is intended for use in humans” (see, e.g., Reutelingsperger, [0069]). Reutelingsperger teaches recombinant AnxA5 protein preparations (see, e.g., Reutelingsperger, [0040], Examples 5-7). Reutelingsperger does not teach that the AnxA5 protein has a His-tag; therefore, one of ordinary skill in the art would readily understand that the AnxA5 protein does not contain a His tag.
Regarding claim 80 pertaining to treating a condition characterized by phosphatidylserine exposed on the biological membrane of pathological cells, Reutelingsperger teaches treatment of tumor cells and neoplastic diseases (see, e.g., Reutelingsperger, abstract). Reutelingsperger teaches diseases in accordance with this invention are, for example, characterized by the expression of phospholipids in the outer layer of a plasma membrane in said subject. Diseases that can be treated and diagnosed are, for example, neoplastic diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, neurodegenerative diseases, and a combination thereof. Specific diseases include ophtalmic disease, gastro/intestinal tract disease, and rheumatoid arthritis” (see, e.g., Reutelingsperger, [0056]).
Regarding claim 82 pertaining to the recombinant AnxA5 protein and sterile container, Reutelingsperger teaches recombinant AnxA5 protein preparations (see, e.g., Reutelingsperger, [0040], Examples 5-7) and teaches “The preparation preferably will be sterile, especially if it is intended for use in humans” (see, e.g., Reutelingsperger, [0069]).
Regarding claim 83 pertaining to the composition, Reutelingsperger teaches that the composition can be made into a pharmaceutically acceptable composition (see, e.g., Reutelingsperger, abstract, [0055]).
Regarding claims 84 and 97 pertaining to the AnxA5 concentration, Reutelingsperger teaches that the concentration of recombinant AnxA5 is 2 mg/ml (see, e.g., Reutelingsperger, [0100], [0101]) (see, e.g., MPEP 2144.05(I)).
Regarding claim 95 pertaining to the gluconoylated AnxA5 protein, Reutelingsperger does not teach that the recombinant AnxA5 protein is gluconoylated; therefore, one of ordinary skill in the art would readily understand that the AnxA5 protein taught by Reutelingsperger is not gluconoylated. Moreover, the Examiner has interpreted gluconoylation of the AnxA5 to be optional since the level of gluconoylated AnxA5 can be 0%.
Regarding claim 96 pertaining to the AnxA5 protein not containing one or more RGD motifs, Reutelingsperger does not teach that the AnxA5 protein has RGD motifs; therefore, one of ordinary skill in the art would readily understand that the AnxA5 protein taught by Reutelingsperger does not contain one or more RGD motifs.
Regarding claim 100 pertaining to the AnxA5 protein being a fusion protein, Reutelingsperger teaches fusion or coupling of a recombinant Annexin A5-Cys2 variant to the fluorescent protein phycoerythrine (see, e.g., Reutelingsperger, Example 6).
Regarding claim 101 pertaining to an amino acid substitution of AnxA5, Reutelingsperger teaches production of Annexin A5-Cys2, wherein “the amino acid Glutamine at position 2 was replaced by the amino acid cysteine” (see, e.g., Reutelingsperger, [0089]).
Regarding claims 112-117 pertaining to treating, preventing, or reducing the risk of diseases, disorders, and infections, “Diseases in accordance with this invention are, for example, characterized by the expression of phospholipids in the outer layer of a plasma membrane in said subject. Diseases that can be treated and diagnosed are, for example, neoplastic diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, neurodegenerative diseases, and a combination thereof. Specific diseases include ophtalmic disease, gastro/intestinal tract disease, and rheumatoid arthritis” (see, e.g., Reutelingsperger, [0056]).
Regarding claim 118 pertaining to parenteral administration, Reutelingsperger teaches “Possible delivery routes of the complexes are subcutaneous, intra-muscular, intra-peritoneal and intravenous administration” (see, e.g., Reutelingsperger, [0060]).
Regarding claim 121 pertaining to the administered dose, Reutelingsperger teaches “Doses range from 0.1 pg/kg to 10 mg/kg in diagnostic procedures and 1 pg/kg to 100 mg/kg in therapeutic procedures. Preferably 1 pg/kg-1 mg/kg (diagnostic) and 5 pg/kg-50 mg/kg (therapeutic). Those skilled in the art would know how to select the appropriate dosages for the specific subject and situation.” (see, e.g., Reutelingsperger, [0060]).
However, Reutelingsperger does not teach: wherein the composition comprises a non-ionic surfactant (claim 79); or wherein the composition comprises an endotoxin content that is at a detectable level, and wherein the detectable level is less than 20 EU per mg AnxA5 protein (claim 79); or wherein the composition comprises host cell nucleic acid of an endotoxin-producing host cell with a cell wall at a detectable level, wherein the detectable level is less than 500 pg per mg of AnxA5 protein (claim 79); or wherein the non-ionic surfactant is a polysorbate (claim 104); or wherein the non-ionic surfactant is polysorbate 80 (claim 105); or wherein the concentration of the non-ionic detergent in the composition is up to 0.1% w/v (claim 106); or wherein the detectable level of endotoxin is less than 10 EU per mg AnxA5 protein (claim 107); or wherein the detectable level of endotoxin is less than 5 EU per mg AnxA5 protein (claim 108); or wherein the detectable level of endotoxin is less than 1 EU per mg AnxA5 protein (claim 109); or wherein the detectable level of host cell nucleic acid of an endotoxin-producing host cell with a cell wall is less than 100 pg per mg of AnxA5 protein (claim 110); or wherein the detectable level of host cell nucleic acid of an endotoxin-producing host cell with a cell wall is less than 10 pg per mg of AnxA5 protein (claim 111).
Kerwin’s general disclosure relates to the use of polysorbates 20 and 80 in biotherapeutics for preventing surface adsorption and as stabilizers for protein aggregation (see, e.g., Kerwin, abstract). Moreover, Kerwin discloses “The concentrations used in the formulations range from 0.0003% (w/v) to 0.3% (w/v). Over the past decade the quality of polysorbate solutions has increased dramatically such that many manufacturers now offer highly purified, low peroxide, and low acid content solutions” (see, e.g., Kerwin, Concluding Remarks, pg. 2932).
Regarding claims 79 and 104-106 pertaining to polysorbate, Kerwin teaches the use of polysorbate 80 in biotherapeutics containing recombinant proteins (see, e.g., Kerwin, abstract & Introduction, pg. 2924), wherein polysorbate 80 is used for preventing surface adsorption and as stabilizers for protein aggregation (see, e.g., Kerwin, abstract). Moreover, Kerwin teaches “The concentrations used in the formulations range from 0.0003% (w/v) to 0.3% (w/v) (see, e.g., Kerwin, Concluding Remarks, pg. 2932).
Park’s general disclosure relates to AnxA5 as a new inhibitor of HMGB1-mediated proinflammatory cytokine production and coagulation in sepsis (see, e.g., Park, abstract). Moreover, Park discloses “that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia in vivo” and that “annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNFα both in vitro and in vivo” (see, e.g., Park, abstract). Furthermore, Park discloses “we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated proinflammation and coagulation in patients with sepsis” (see, e.g., Park, abstract).
Regarding claims 79 and 107-111 pertaining to the endotoxin and host cell nucleic acid content, Park teaches “Endotoxin was removed from purified proteins by using Triton X-114 Surfact-Amps detergent (Thermo Scientific). Endotoxin level (less than 0.1 EU/ mg protein), and the level of bacterial DNA (0.1 ng/mg protein) were assessed using Limulus amoebocyte lysate (LAL) QCL-1000 (LONZA Ltd.) and Picogreen assays (Invitrogen), respectively” (see, e.g., Park, “DNA Constructs and Protein Preparation”, pgs. 425-426).
Petsch’s general disclosure relates to “an overview of the properties of endotoxins and the significance of endotoxin contamination, this review intends to provide an overall picture of the various methods employed for their removal” (see, e.g., Petsch, abstract).
Regarding claims 79 and 107-111 pertaining to endotoxin levels, Petsch teaches “Endotoxins liberated by gram-negative bacteria are frequent contaminations of protein solutions derived from bioprocesses. Because of their high toxicity in vivo and in vitro, their removal is essential for a safe parenteral administration” (see, e.g., Petsch, abstract).
Takeda’s general disclosure relates to a method “for purifying physiologically active proteins, especially antibodies, in order to remove impurities such as DNA contaminants and viruses with minimal loss of physiologically active proteins. The physiologically active protein is introduced into an aqueous solution of low conductivity at a pH of below the isoelectric point of the physiologically active protein to precipitate impurities as particles. The particles are removed, leaving a purified physiologically active protein” (see, e.g., Takeda, abstract).
Regarding claims 79 and 107-111 pertaining to host cell nucleic acid levels, Takeda teaches that in recombinantly-produced physiologically active protein-containing formulations there is a need to remove host DNA and impurities and that under the World Health Organization (WHO) criteria, the amount of DNA in biological drugs should not exceed 100 pg DNA/dose (see, e.g., Takeda, col. 1, lines 20-25).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer Reutelingsperger’s AnxA5 composition for treatment of diseases and disorders, wherein the composition comprises polysorbate 80, as taught by Kerwin. One would have been motivated to do so because Kerwin teaches that polysorbate 80 is “used in the formulation of biotherapeutic products for both preventing surface adsorption and as stabilizers against protein aggregation” (see, e.g., Kerwin, abstract). Moreover, Reutelingsperger teaches production and administration of compositions comprising recombinant AnxA5 (see, e.g., Reutelingsperger, abstract). Therefore, based on the teachings of Reutelingsperger and Kerwin, it would have been obvious to include polysorbate 80 into the AnxA5 composition in order for both preventing surface adsorption and as stabilizers against protein aggregation. One would have expected success because Reutelingsperger and Kerwin both teach biotherapeutic compositions containing proteins.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Reutelingsperger’s AnxA5 composition for treatment of diseases and disorders, wherein the composition has an endotoxin level less than 0.1 EU/mg protein and a bacterial DNA level of 0.1 ng/mg protein, as taught by Park. One would have been motivated to do so because Park teaches removal of endotoxin and bacterial DNA from the AnxA5 protein preparation (see, e.g., Park, “DNA Constructs and Protein Preparation”, pg. 425). Furthermore, Petsch teaches that endotoxins are frequent contaminations of protein solutions and because of their high toxicity in vitro and in vivo, their removal is essential for safe parenteral administration (see, e.g., Petsch, abstract). Additionally, Takeda teaches that it is essential to remove host cell DNA from recombinant protein preparations, and that the WHO criteria requires the amount of DNA in a protein therapeutic preparation to not exceed 100 pg DNA/dose (see, e.g., Takeda, col. 1, lines 20-25). Moreover, Reutelingsperger teaches production and administration of a recombinant AnxA5 preparation (see, e.g., Reutelingsperger, abstract). Therefore, based on the teachings of Reutelingsperger, Park, Petsch, and Takeda, it would have been obvious to produce a recombinant AnxA5 protein preparation wherein endotoxin and host cell DNA are removed. One would have expected success because Reutelingsperger, Park, Petsch, and Takeda all teach recombinant protein therapeutic formulations.
Claims 81 and 102-103 are rejected under 35 U.S.C. 103 as being unpatentable over Reutelingsperger, Kerwin, Park, Petsch, and Takeda as applied to claims 79-80, 82-84, 95-97, 100-101, 104-118, and 121 above, and further in view of Learmonth (Novel isoforms of CaBP 33/37 (annexin V) from mammalian brain: structural and phosphorylation differences that suggest distinct biological roles; 1992).
The teachings of Reutelingsperger, Kerwin, Park, Petsch, and Takeda herein referred to as modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda, are discussed above as it pertains to a method of treating a subject in need thereof with a sterile composition comprising a recombinant AnxA5 protein and a non-ionic surfactant, wherein the composition comprises an endotoxin and host cell nucleic acid content.
However, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda does not teach: wherein the AnxA5 protein differs from the sequence of human Annexin A5 (SEQ ID NO: 1) at one or more positions by an amino acid insertion or deletion or substitution, wherein the AnxA5 protein is more than 95% identical to SEQ ID NO: 1 and the amino acid sequence is not the same as a mammalian orthologue of human Annexin A5 (claim 81); or wherein the amino acid substitution is a conservative substitution (claim 102); or wherein the conservative substitution is Gly, Ala (claim 103).
Learmonth’s general disclosure relates to purification of two annexin V isoforms, CaBP33 and CaBP37, which are calcium-dependent phospholipid- and membrane-binding proteins (see, e.g., Learmonth, abstract). Moreover, Learmonth discloses two amino acid substitution difference between the two isoforms (see, e.g., Learmonth, abstract).
Regarding claims 81 and 102-102, Learmonth teaches a bovine annexin V (i.e., annexin A5) sequence with 96.6% sequence similarity to human annexin A5, and which has one or more amino acid substitutions (see, e.g., Learmonth & Office Action Appendix). Moreover, this sequence has a conservative Gly, Ala substitution at position 293 (see, e.g., Office Action Appendix).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce and administer modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda’s AnxA5 composition for treatment of diseases and disorders, wherein the AnxA5 protein is a bovine AnxA5 protein with 96.6% sequence similarity to human AnxA5 and containing amino acid substitutions, as taught by Learmonth. One would have been motivated to do so because Learmonth teaches that the bovine isoforms isolated are calcium-dependent phospholipid- and membrane-binding proteins (see, e.g., Learmonth, abstract), which one of ordinary skill in the art would readily understand means they are AnxA5 isoforms. Additionally, Learmonth teaches that these isoforms can undergo different amino acid substitutions and phosphorylation to have structural differences that result in distinct biological roles (see, e.g., Learmonth, abstract). Learmonth teaches that “The Glu [Wingdings font/0xE0] Lys substitution has a large effect on the apparent molecular weight and other chromatographic properties of annexin V” and that “The Lys-to-Glu substitution described here would result in a net change of two charges on the surface of annexin V which could markedly affect phospholipid binding” (see, e.g., Learmonth, pgs. 82-83). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches AnxA5 protein preparations (see, e.g., Reutelingsperger, abstract), wherein “binds to at least one negatively charged phospholipid and facilitates internalization of the pharmaceutical compound into a cell” (see, e.g., Reutelingsperger, [0044]). Therefore, based on the teachings of modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Learmonth, it would have been obvious to utilize AnxA5 isoforms or variants in order to alter phospholipid binding. One would have expected success because modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Learmonth both teach AnxA5.
Claims 85-93 are rejected under 35 U.S.C. 103 as being unpatentable over Reutelingsperger, Kerwin, Park, Petsch, and Takeda as applied to claims 79-80, 82-84, 95-97, 100-101, 104-118, and 121 above, and further in view of Logue (Expression, purification and use of recombinant annexin V for the detection of apoptotic cells; 2009 – cited in the IDS filed on 08/04/2023).
The teachings of Reutelingsperger, Kerwin, Park, Petsch, and Takeda herein referred to as modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda, are discussed above as it pertains to a method of treating a subject in need thereof with a sterile composition comprising a recombinant AnxA5 protein and a non-ionic surfactant, wherein the composition comprises an endotoxin and host cell nucleic acid content.
Regarding claims 85-86 pertaining to the composition, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches “The preparation preferably will be sterile, especially if it is intended for use in humans” (see, e.g., Reutelingsperger, [0069]). Additionally, modified-Reutelingsperger-Kerwin-Park teaches the use of polysorbate 80 in biotherapeutics containing recombinant proteins (see, e.g., Kerwin, abstract & Introduction, pg. 2924), wherein polysorbate 80 is used for preventing surface adsorption and as stabilizers for protein aggregation (see, e.g., Kerwin, abstract). Moreover, modified-Reutelingsperger-Kerwin-Park teaches “The concentrations used in the formulations range from 0.0003% (w/v) to 0.3% (w/v) (see, e.g., Kerwin, Concluding Remarks, pg. 2932).
Regarding claims 90-92 pertaining to the host cell, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches that the host cell for producing recombinant AnxA5 is Escherichia coli (see, e.g., Park, “DNA Constructs and Protein Preparation”, pg. 425). One of ordinary skill in the art would readily understand that Escherichia coli is a Gram negative, endotoxin-producing, prokaryote.
However, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda does not teach: wherein the composition comprises the sterile AnxA5 protein product in a non-phosphate buffer at about pH 7.4, comprising about 150 mM NaCl, about 1 mM CaCl2, about 0.05% (w/w) polysorbate or other non-ionic detergent (claim 85); or wherein the non-phosphate buffer is Bis-Tris or Tris- buffer (claim 86); or wherein the composition comprises NaCl at a concentration that maintains AnxA5 protein in a form that is predominantly monomeric (claim 87); or wherein the composition comprises non-AnxA5 protein at a level less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5 ng per mg of AnxA5 protein (claim 88); or wherein the non-AnxA5 protein is a host cell protein (claim 89); or wherein the host cell protein is at a detectable level, albeit less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5 ng per mg of AnxA5 protein in the composition (claim 93).
Logue’s general disclosure relates to “protocols for bacterial expression, purification and FITC labeling of recombinant annexin V. By following the method outlined in this protocol, it is possible to produce milligram amounts of recombinant annexin V within 3 d. We also describe a method for the assessment of annexin V binding to cell populations by flow cytometry or fluorescence microscopy” (see, e.g., Logue, abstract).
Regarding claim 85 pertaining to the composition, Logue teaches that the Annexin V binding buffer, which is used for experiments with recombinant annexin V, contains “10 mM of HEPES-NaOH (pH 7.4), 150 mM of NaCl, 5 mM of KCl, 1 mM of MgCl2, 1.8 mM of CaCl2” (see, e.g., Logue, “Annexin V binding buffer”, pg. 1387).
Regarding claim 86 pertaining to the non-phosphate buffer, Logue teaches buffers for SDS-PAGE that contain Tris (see, e.g., Logue, “Reagent Setup”, pg. 1387).
Regarding claim 87 pertaining to the concentration of NaCl, Logue teaches “For annexin V to bind PS efficiently, calcium is required at a concentration of 1–3 mM. Annexin V binding buffer should therefore contain calcium. For most cell types, a concentration of 1.8 mM calcium is ideal, as higher concentrations can result in nonspecific binding of annexin V to other phospholipids” (see, e.g., Logue, “Calcium concentration”, pg. 1386). Moreover, annexin V inherently binds phosphatidylserine as a monomer (see, e.g., Van Genderen – Art of Record).
Regarding claims 88-89 and 93 pertaining to the host cell protein, Logue teaches an SDS-PAGE gel that shows all the proteins loaded onto the gel (see, e.g., Logue, Figure 2). AnxA5 is shown in elution #1-#3 lanes; however, other host cell proteins are represented as the other bands of the SDS-PAGE gel (see, e.g., Logue, Figure 2). One of ordinary skill in the art would readily understand that the other host cell proteins, that are not AnxA5, can be measured from the bands in the SDS-PAGE gel.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda’s recombinant AnxA5 protein composition, wherein the composition comprises a non-phosphate buffer, such as Tris buffer, as taught by Logue. One would have been motivated to do so because Logue teaches that Tris buffer can be used with AnxA5 in order to purify AnxA5 using affinity chromatography (see, e.g., Logue, Protocol, pgs. 1388-1389). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches an AnxA5 recombinant protein composition that is purified in order to improve the quality to the compound (see, e.g., Reutelingsperger, [0007]). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches purification of recombinant AnxA5 from E. coli using ion-exchange and gel-permeation chromatography (see, e.g., Reutelingsperger, Example 4). Therefore, based on the teachings of modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Logue, it would have been obvious to use Tris buffer in order to purify the AnxA5 composition. One would have expected success because modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Logue both teach AnxA5, in general, as well as purification techniques for recombinant AnxA5.
Regarding claims 88 and 93’s concentration limitations, those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., concentration or amount of a compound) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan (see, e.g., MPEP 2144.05). For example, Logue teaches SDS-PAGE gel that shows all the proteins loaded onto the gel (see, e.g., Logue, Figure 2). AnxA5 is shown in elution #1-#3 lanes; however, other host cell proteins are represented as the other bands of the SDS-PAGE gel (see, e.g., Logue, Figure 2). Furthermore, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teach “Any substance may be removed as an impurity by the method of the present invention as long as it is not a target protein to be purified. Examples of such impurities include DNA contaminants, viruses, Protein A (eluted from columns), endotoxins, HCP (host cell-derived proteins), as well as medium components Hy-Fish(FL) and IGF, with DNA contaminants or viruses being preferred” (see, e.g., Logue, col. 6, lines 9-15). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches “Based on the detailed description, various changes and modifications will be apparent to those skilled in the art, and such changes and modifications fall within the scope of the invention” (see, e.g., Logue, col. 8, lines 64-67). Therefore, one of ordinary skill in the art would readily understand that that the other host cell proteins, that are not AnxA5, can be measured from the bands in the SDS-PAGE gel, and that the amount of other host cell proteins depends on the purity of the sample and the amount of sample loaded into the SDS-PAGE gel. This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal, which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning the concentration, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Claim 94 is rejected under 35 U.S.C. 103 as being unpatentable over Reutelingsperger, Kerwin, Park, Petsch, and Takeda as applied to claims 79-80, 82-84, 95-97, 100-101, 104-118, and 121 above, and further in view of Gardner (U.S. Patent No. 8,173,396; Date of Publication: May 8, 2012).
The teachings of Reutelingsperger, Kerwin, Park, Petsch, and Takeda herein referred to as modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda, are discussed above as it pertains to a method of treating a subject in need thereof with a sterile composition comprising a recombinant AnxA5 protein and a non-ionic surfactant, wherein the composition comprises an endotoxin and host cell nucleic acid content.
However, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda does not teach: wherein the composition comprises gluconoylated AnxA5 protein within a range selected from the group consisting of 0.5 to 30%, 0.5 to 20%, 0.5 to 15%, and 0.5 to 10% of the total content of AnxA5 protein in the product (claim 94).
Gardner’s general disclosure relates to “The present invention also provides methods for preventing gluconoylation of polypeptides expressed by microorganisms that include introducing (e.g., transforming, infecting or transfecting) DNA encoding a polypeptide that demonstrates pgl activity into the microorganism. This polypeptide may be a phosphogluconolactonase enzyme” (see, e.g., Gardner, col. 3, lines 24-26). Moreover, Gardner discloses “A method for expressing or overexpressing polypeptides in a microorganism, such as E. coli, with a reduced incidence of phosphogluconoylation during fermentation is greatly needed. In addition, creation of a totally phage free BL21 (DE3) host cell would be highly desirable for the manufacture of therapeutic recombinant proteins in the E. coli format” (see, e.g., Gardner, col 3, lines 16-21).
Regarding claim 94 pertaining to the percentage of gluconoylated AnxA5, Gardner teaches that culturing a cell, such as E. coli, in medium supplemented or made rich with yeast extract and tryptone results in undetectable amounts of gluconoylated protein; however, culturing in minimal medium results in 34% of the recombinant proteins being gluconoylated (see, e.g., Gardner, Example 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda’s recombinant AnxA5 protein composition, wherein the recombinant AnxA5 has low or undetectable amounts of gluconoylation, as taught by Gardner. One would have been motivated to do so because “Cellular stresses arising from growth on minimal medium, high cell densities, and high-level heterologous polypeptide expression, among other stresses, may contribute to the gluconoylation of heterologous polypeptide. Alleviating one or more of these stressors may therefore affect the level of gluconoylation of protein expressed in the microorganism, which in turn may effect the purity and titer yield of a desired polypeptide. Some strains of E. coli may have higher levels of pgl activity than others (although the gene responsible for this activity has not been identified in E. coli. Cordwell, S. J. 1999. Arch. Microbiol. 172:269-279. Furthermore, gluconoylation of polypeptides may affect crystallization and structural determination of these polypeptides” (see, e.g., Gardner, col. 10,lines 25-37). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches a recombinant AnxA5 composition (see, e.g., Reutelingsperger, abstract), wherein annexins crystallize at the membrane surface during phospholipid membrane binding (see, e.g., Reutelingsperger, [0029]). Therefore, based on the teachings of modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Gardner, it would have been obvious to produce a recombinant AnxA5 protein composition that has little to no gluconoylation of AnxA5 because gluconoylation affects annexin crystallization. One would have expected success because modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Gardner both teach recombinant protein compositions.
Regarding claims 94’s percentage limitations, those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., concentration or amount of a compound) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan (see, e.g., MPEP 2144.05). For example, Gardner teaches “Cellular stresses arising from growth on minimal medium, high cell densities, and high-level heterologous polypeptide expression, among other stresses, may contribute to the gluconoylation of heterologous polypeptide. Alleviating one or more of these stressors may therefore affect the level of gluconoylation of protein expressed in the microorganism, which in turn may effect the purity and titer yield of a desired polypeptide. Some strains of E. coli may have higher levels of pgl activity than others (although the gene responsible for this activity has not been identified in E. coli. Cordwell, S. J. 1999. Arch. Microbiol. 172:269-279. Furthermore, gluconoylation of polypeptides may affect crystallization and structural determination of these polypeptides” (see, e.g., Gardner, col. 10,lines 25-37). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teach production of recombinant AnxA5 proteins, wherein AnxA5 proteins crystallize at the membrane surface in when binding to phospholipids (see, e.g., Reutelingsperger, [0029]). Therefore, based on these teachings, one of ordinary skill in the art would want to reduce gluconoylation of recombinant proteins. This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal, which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning the concentration, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Claims 98-99 are rejected under 35 U.S.C. 103 as being unpatentable over Reutelingsperger, Kerwin, Park, Petsch, and Takeda as applied to claims 79-80, 82-84, 95-97, 100-101, 104-118, and 121 above, and further in view of Allison (US 2003/0166532; Date of Publication: September 4, 2003).
The teachings of Reutelingsperger, Kerwin, Park, Petsch, and Takeda herein referred to as modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda, are discussed above as it pertains to a method of treating a subject in need thereof with a sterile composition comprising a recombinant AnxA5 protein and a non-ionic surfactant, wherein the composition comprises an endotoxin and host cell nucleic acid content.
However, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda does not teach: wherein the AnxA5 protein is chemically modified (claim 98); or wherein the AnxA5 protein is chemically modified by PEGylation (claim 99).
Allison’s general disclosure relates to “A modified annexin protein, preferably annexin V, is used to prevent thrombosis without increasing hemorrhage. Annexin binds to phosphatidylserine on the outer surface of cell membranes, thereby preventing binding of the prothrombinase complex necessary for thrombus formation. It does not, however, affect platelet aggregation necessary for hemostasis. The modified annexin molecule can be a homodimer of annexin, an annexin molecule coupled to one or more polyethylene glycol chains, or an annexin molecule coupled to another protein. By increasing the molecular weight of annexin, the modified annexin is made to remain in circulation for sufficient time to provide a sustained therapeutic effect” (see, e.g., Allison, abstract).
Regarding claims 98-99 pertaining to a PEGylated AnxA5 protein, Allison teaches “the present invention provides an isolated modified annexin protein containing an annexin protein, preferably annexin V, coupled to polyethylene glycol (PEG)” (see, e.g., Allison, [0016]). Moreover, Allision teaches PEGylation of annexin V using the EDC plus sulfo-NHS procedure (see, e.g., Allison, Example 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda’s recombinant AnxA5 composition, wherein the recombinant AnxA5 protein is PEGylated, as taught by Allison. One would have been motivated to do so because Allison teaches “PEG derivatives have been widely used in covalent attachment (referred to as pegylation) to proteins to enhance solubility, as well as to reduce immunogenicity, proteolysis, and kidney clearance. The superior clinical efficacy of recombinant products coupled to PEG is well established” (see, e.g., Allison, [0028]). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches administration of a recombinant AnxA5 composition for treatment of “diseases, such as neoplastic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases” (see, e.g., Reutelingsperger, abstract). Therefore, based on the teachings of modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Allison, it would have been obvious to PEGylate the recombinant AnxA5 protein in order to “enhance solubility, as well as to reduce immunogenicity, proteolysis, and kidney clearance” (see, e.g., Allison, [0028]). One would have expected success because modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Allison both teach recombinant AnxA5 protein compositions for treatment of diseases.
Claims 119-120 and 122 are rejected under 35 U.S.C. 103 as being unpatentable over Reutelingsperger, Kerwin, Park, Petsch, and Takeda as applied to claims 79-80, 82-84, 95-97, 100-101, 104-118, and 121 above, and further in view of Thorpe (US 2006/0228299; Date of Publication: October 12, 2006 ).
The teachings of Reutelingsperger, Kerwin, Park, Petsch, and Takeda herein referred to as modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda, are discussed above as it pertains to a method of treating a subject in need thereof with a sterile composition comprising a recombinant AnxA5 protein and a non-ionic surfactant, wherein the composition comprises an endotoxin and host cell nucleic acid content.
However, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda does not teach: wherein the topical administration is a cream, an ointment, ophthalmic drop, or otic drop (claim 119); or wherein AnxA5 protein is administered to an adult subject at a daily dosage of from 0.01 to 1000 mg of AnxA5 protein (claim 120); or wherein AnxA5 protein is administered to the subject as a unit dosage form, and wherein the unit dosage form contains about 1, 2, 3, 4, 5, 6, 7, 8,9, 10 mg of the AnxA5 protein (claim 122).
Thorpe’s general disclosure relates to “new phosphatidylserine binding constructs with surprising combinations of properties, and a range of diagnostic and therapeutic conjugates thereof. The new constructs effectively bind phosphatidylserine targets in disease and enhance their destruction, and can also specifically deliver attached imaging or therapeutic agents to the disease site. Also disclosed are methods of using the new construct compositions, therapeutic conjugates and combinations thereof in tumor vasculature targeting, cancer diagnosis and treatment, and for treating viral infections and other diseases” (see, e.g., Thorpe, abstract).
Regarding claims 119-120 and 122 pertaining to the dosage form of the composition, Thorpe teaches annexin V (i.e., annexin A5) may be used in the invention to bind phosphatidylserine (see, e.g., Thorpe, [0024]). Thorpe teaches that the formulations suitable for topical administration of the composition include ointments, creams, gels, and pastes (see, e.g., Thorpe, [0466]). Furthermore, Thorpe teaches “Accordingly, using this information, the inventors contemplate that useful low doses for human administration will be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or about 30 mgs or so per patient; and useful high doses for human administration will be about 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or about 500 mgs or so per patient. Useful intermediate doses for human administration are contemplated to be about 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200 or about 225 mgs or so per patient. In general, dosage ranges of between about 5-100 mgs, about 10-80 mgs, about 20-70 mgs, about 25-60 mgs, or about 30-50 mgs per patient will be preferred. However, any particular range using any of the foregoing recited exemplary doses or any value intermediate between the particular stated ranges is contemplated” (see, e.g., Thorpe, [0535]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda’s recombinant AnxA5 protein composition, wherein the composition is formulated for administration at various dosages, as taught by Thorpe. One would have been motivated to do so because Thorpe teaches phosphatidylserine binding constructs, such as AnxA5, wherein these constructs are formulated to “tumor vasculature targeting and cancer treatment, and for treating viral infections and other diseases” (see, e.g., Thorpe, [0013]). Additionally, Thorpe teaches that the annexin formulations can be formulated for topical administration in order to deliver the composition to the skin (see, e.g., Thorpe, [0466]). Furthermore, Thorpe teaches that the intention of the therapeutic regimen is to produce significant anti-tumor effects while keeping the dose below a certain level to reduce toxicity (see, e.g., Thorpe, [0537]). Moreover, modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda teaches an administration of a recombinant AnxA5 composition for treatment of “diseases, such as neoplastic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases” (see, e.g., Reutelingsperger, abstract). Therefore, based on the teachings of modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Thorpe, it would have been obvious to formulate the AnxA5 composition into a topical formulation for administration at a certain dose to treat a specific disease. One would have expected success because modified-Reutelingsperger-Kerwin-Park-Petsch-Takeda and Thorpe both teach treatment of diseases by administering AnxA5.
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 79 and 81-111 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,773,134 (herein referred to as US’134). Although the claims at issue are not identical, they are not patentably distinct from each other because US’134 pertains to a composition comprising a recombinant AnxA5 protein and the instant application pertains to a method of treating a human or animal in need thereof by administering the same AnxA5 composition claimed in US’134. Furthermore, the instant application and US’134 set forth substantially similar claims related to a composition comprising AnxA5. US’134 teaches A composition comprising a recombinant AnxA5 protein, wherein said AnxA5 protein differs from the sequence of human Annexin A5 (SEQ ID NO:1) at one or more positions by an amino acid insertion or deletion or substitution, wherein the AnxA5 protein is more than 95% identical to SEQ ID NO: 1 and the amino acid sequence is not the same as a mammalian orthologue of human Annexin A5, and wherein: (a) the composition is a sterile composition; (b) the composition is in a sterile container; (c) the composition comprises non-ionic surfactant; (d) the composition comprises an endotoxin content that is at a detectable level, and wherein the detectable level is less than 20 EU per mg AnxA5 protein; (e) the composition comprises host cell nucleic acid of an endotoxin-producing host cell with a cell wall at a detectable level, wherein the detectable level is less than 500 pg per mg of AnxA5 protein; and (f) the AnxA5 protein does not contain a His-tag (see, e.g., US’134, claim 1); wherein the composition is a pharmaceutically acceptable and/or veterinarily acceptable composition (see, e.g., US’134, claim 2); wherein the composition contains the AnxA5 protein at a concentration selected from the group consisting of at least about 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 50 mg/mL, 100 or greater (see, e.g., US’134, claim 3); wherein the composition comprises a sterile AnxA5 protein product in a non-phosphate buffer at about pH 7.4, comprising about 150 mM NaCl, about 1 mM CaCl.sub.2), about 0.05% (w/w) polysorbate or other non-ionic detergent (see, e.g., US’134, claim 4); wherein the non-phosphate buffer is Bis-Tris or Tris-buffer and the polysorbate is polysorbate 80 (see, e.g., US’134, claim 5); wherein the concentration of the AnxA5 protein in the final sterile AnxA5 protein product is about 10 mg/mL (see, e.g., US’134, claim 6); wherein the composition comprises NaCl at a concentration that maintains AnxA5 protein in a form that is predominantly monomeric (see, e.g., US’134, claim 7); wherein the composition comprises non-AnxA5 protein at a level less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 ng per mg of AnxA5 protein (see, e.g., US’134, claim 8); wherein the non-AnxA5 protein is a host cell protein (see, e.g., US’134, claim 9); wherein the host cell is a prokaryotic cell (see, e.g., US’134, claim 10); wherein the prokaryotic cell is a Gram positive or Gram negative cell (see, e.g., US’134, claim 11); wherein the Gram negative cell is an endotoxin-producing Gram negative bacterial cell (see, e.g., US’134, claim 12); wherein the host cell protein is at a detectable level albeit less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 ng per mg of AnxA5 protein in the composition (see, e.g., US’134, claim 13); wherein: the composition comprises gluconoylated AnxA5 protein within a range selected from the group consisting of 0.5 to 30%, 0.5 to 20%, 0.5 to 15%, and 0.5 to 10% of the total content of AnxA5 protein in the product (see, e.g., US’134, claim 14); wherein: the composition has a level of gluconoylated AnxA5 protein below 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%, or a level of gluconoylated AnxA5 protein that is 0% (see, e.g., US’134, claim 15); wherein: the AnxA5 protein does not contain one or more RGD motifs (see, e.g., US’134, claim 16); wherein the AnxA5 protein is chemically modified (see, e.g., US’134, claim 17); wherein the AnxA5 protein is chemically modified by PEGylation (see, e.g., US’134, claim 18); wherein the AnxA5 protein is a fusion protein comprising an AnxA5 protein and a fusion partner (see, e.g., US’134, claim 19); wherein said AnxA5 protein differs from the sequence of human Annexin A5 (SEQ ID NO:1) by an amino acid substitution at one or more positions (see, e.g., US’134, claim 20); wherein the, or each, amino acid substitution is a conservative substitution (see, e.g., US’134, claim 21); wherein the, or each, conservative substitution is selected from the group consisting of Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr (see, e.g., US’134 claim 22); wherein the non-ionic surfactant is a polysorbate (see, e.g., US’134, claim 23); wherein the non-ionic surfactant is polysorbate 80 (see, e.g., US’134, claim 24); wherein the concentration of the non-ionic detergent in the composition is up to 0.1% w/v (see, e.g., US’134, claim 25); wherein the detectable level of endotoxin is less than 10 EU per mg AnxA5 protein (see, e.g., US’134, claim 26); wherein the detectable level of endotoxin is less than 5 EU per mg AnxA5 protein (see, e.g., US’134, claim 27); wherein the detectable level of endotoxin is less than 1 EU per mg AnxA5 protein (see, e.g., US’134, claim 28); wherein the detectable level of host cell nucleic acid of an endotoxin-producing host cell with a cell wall is less than 100 pg per mg of AnxA5 protein (see, e.g., US’134, claim 29); wherein the detectable level of host cell nucleic acid of an endotoxin-producing host cell with a cell wall is less than 10 pg per mg of AnxA5 protein (see, e.g., US’134, claim 30). Therefore, the composition claimed in US’134 is the same composition being claimed in the instantly claimed invention, wherein in the instantly claimed invention this composition is being administered to a subject in need thereof. Furthermore, the instant claimed invention is merely of administering the composition claimed in US’134.
Claims 80, 112-118, and 121 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,773,134 (herein referred to as US’123) in view of Reutelingsperger (US 2006/0009381; Date of Publication: January 12, 2006 – cited in the IDS filed on 08/04/2023 – cited above).
Claims 1-30 of US’134 are discussed above.
However, US’134 does not teach: wherein the method is a method of treating a condition characterised by phosphatidylserine exposed on the biological membrane of pathological cells, or virus; or a method of treating, preventing or reducing the risk of retinal vein occlusion; or a method of treating, preventing or reducing the risk of developing a cardiovascular disease; a method of treating, preventing, or reducing the rate of, the transmission of a viral infection; or a method of treating, preventing or reducing the risk of vascular dysfunction; or a method of treating, preventing or reducing the risk of haematological disorders; or wherein the composition is administered to the subject parenterally.
The teachings of Reutelingsperger are discussed above.
Regarding claims 80 and 112-117 pertaining to treatment and prevention of diseases, Reutelingsperger teaches “Diseases in accordance with this invention are, for example, characterized by the expression of phospholipids in the outer layer of a plasma membrane in said subject. Diseases that can be treated and diagnosed are, for example, neoplastic diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, neurodegenerative diseases, and a combination thereof. Specific diseases include ophtalmic disease, gastro/intestinal tract disease, and rheumatoid arthritis” (see, e.g., Reutelingsperger, [0056]).
Regarding claim 118 pertaining to administration route, Reutelingsperger teaches “Possible delivery routes of the complexes are subcutaneous, intra-muscular, intra-peritoneal and intravenous administration” (see, e.g., Reutelingsperger, [0060]).
Regarding claim 121 pertaining to the daily dosage of AnxA5, Reutelingsperger teaches “Doses range from 0.1 pg/kg to 10 mg/kg in diagnostic procedures and 1 pg/kg to 100 mg/kg in therapeutic procedures. Preferably 1 pg/kg-1 mg/kg (diagnostic) and 5 pg/kg-50 mg/kg (therapeutic). Those skilled in the art would know how to select the appropriate dosages for the specific subject and situation.” (see, e.g., Reutelingsperger, [0060]).
It would have been obvious to one or ordinary skill in the art to administer the AnxA5 composition, as taught by Reutelingsperger, to a subject in need thereof, because Reutelingsperger teaches that administration of AnxA5 can be used to treat diseases, such as “neoplastic diseases, cardiovascular diseases, infectious diseases, autoimmune diseases, neurodegenerative diseases, and a combination thereof. Specific diseases include ophtalmic disease, gastro/intestinal tract disease, and rheumatoid arthritis” (see, e.g., Reutelingsperger, [0056]).
Claims 119-120 and 122 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,773,134 (herein referred to as US’123) in view of Thorpe (US 2006/0228299; Date of Publication: October 12, 2006 – cited above).
Claims 1-30 of US’134 are discussed above.
However, US’134 does not teach: wherein the topical administration is a cream, an ointment, ophthalmic drop, or otic drop; or wherein AnxA5 protein is administered to an adult subject at a daily dosage of from 0.01 to 1000 mg of AnxA5 protein; or wherein AnxA5 protein is administered to the subject as a unit dosage form, and wherein the unit dosage form contains about 1, 2, 3, 4, 5, 6, 7, 8,9, 10 mg of the AnxA5 protein.
Regarding claims 119-120 and 122 pertaining to the dosage form of the composition, Thorpe teaches annexin V (i.e., annexin A5) may be used in the invention to bind phosphatidylserine (see, e.g., Thorpe, [0024]). Thorpe teaches that the formulations suitable for topical administration of the composition include ointments, creams, gels, and pastes (see, e.g., Thorpe, [0466]). Furthermore, Thorpe teaches “Accordingly, using this information, the inventors contemplate that useful low doses for human administration will be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or about 30 mgs or so per patient; and useful high doses for human administration will be about 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or about 500 mgs or so per patient. Useful intermediate doses for human administration are contemplated to be about 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200 or about 225 mgs or so per patient. In general, dosage ranges of between about 5-100 mgs, about 10-80 mgs, about 20-70 mgs, about 25-60 mgs, or about 30-50 mgs per patient will be preferred. However, any particular range using any of the foregoing recited exemplary doses or any value intermediate between the particular stated ranges is contemplated” (see, e.g., Thorpe, [0535]).
It would have been obvious to one of ordinary skill in the art to administer an AnxA5 therapeutic composition to a subject in need thereof, wherein the composition is administered topically at various dosages in order to deliver the composition to the skin (see, e.g., Thorpe, [0466]).
Art of Record
van Genderen HO, Kenis H, Hofstra L, Narula J, Reutelingsperger CP. Extracellular annexin A5: functions of phosphatidylserine-binding and two-dimensional crystallization. Biochim Biophys Acta. 2008 Jun;1783(6):953-63. doi: 10.1016/j.bbamcr.2008.01.030. Epub 2008 Feb 20. PMID: 18334229.
Conclusion
Claims 79-122 are rejected.
No claims are allowed.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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