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 .
Priority
Acknowledgement is made that the instant application is a National Stage of International application No. PCT/CN2023/098693 (filed 06/06/2023). Acknowledgement is made of Applicants’ claim for priority to Chinese application CN202210633900.4 (filed 06/07/2022). A copy of the foreign priority document is present in the application file.
Claim Objections
Claims 30, 31, 33-36, and 49 are objected to because of the following informalities:
Claim 30 recites the pharmaceutical composition comprises a recombinant adeno-associated virus and a buffer… However, several more components of the pharmaceutical composition are listed after “a buffer” without any conjunction.
Claim 31 recites the abbreviations HS15 and TPGS without defining the full term. The full term should precede the first occurrence of an abbreviation.
Claim 36 recites the abbreviation P188 without defining the full term. The full term should precede the first occurrence of an abbreviation.
Claims 33-36 do not include a conjunction and therefore it is unclear whether the pharmaceutical composition requires all the listed concentrations or whether the claims requires any of the components to be at the listed concentrations.
Claim 49 does not comprise a conjunction thus it is unclear if the pharmaceutical composition is required to be all the listed formulations or any of the listed formulations.
Appropriate correction is required.
Claim Interpretation
Claim 30 is being interpreted as requiring a pharmaceutical composition comprising recombinant adeno-associated virus, a buffer, an amino acid, a stabilizer, and a nonionic surfactant, wherein the buffer is a citrate buffer.
Claims 33-36 are being interpreted including the conjunction “and” i.e. as requiring all of the listed concentrations of all the listed components.
The abbreviation P188, in claim 36, is being interpreted as poloxamer 188.
In claim 44, the limitation “an antibody or a protein comprises at least 80% identity to the above antibody or protein” is being interpreted as referring to any protein with at least 80% sequence identity to the protein of claim 44 a) or b) and any antibody having at least 80% sequence identity to the heavy and light chain variable regions of claim 44 c) or d).
Claim 47 recites the limitation “a nucleotide sequence of SEQ ID NO: 9”. Under BRI, a nucleotide sequence means any 2 or more nucleotides. Thus, the claim is being interpreted as requiring any 2 or more nucleotides found in SEQ ID NO: 9. If applicants intend for the claim to require the entire nucleotide sequence of SEQ ID NO: 9, the claim should be amended to recite the nucleotide sequence of SEQ ID NO: 9.
Claim 49 is being interpreted as including the conjunction “or”, i.e. the formulations are presented as alternatives.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 56-58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 56-58 are drawn to a method for treating a VEGF-related disease, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an rAAV, a citrate buffer, an amino acid, a stabilizer, and a nonionic surfactant. The specification does not reasonably provide enablement for treating a VEGF-related disease by administering a pharmaceutical composition comprising any rAAV. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the invention commensurate in scope with these claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Claims 56 recites a method for treating a VEGF-related disease, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 30 to a subject in need. The pharmaceutical composition of claim 30 comprises a rAAV, a citrate buffer, an amino acid, a stabilizer, and a nonionic surfactant. The composition of claim 30 does not require the rAAV to express any nucleic acid or coding sequence. The breadth of the claims thus covers treating a VEGF-related disease with a pharmaceutical composition comprising any rAAV. Thus, the scope of the claims covers a pharmaceutical composition comprising an rAAV encoding any nucleic acid sequence or even an empty rAAV which does not comprise any coding sequence.
The nature of the invention is adenoviral based therapies, specifically using adenoviral based therapies to treat VEGF related diseases. Adenoviral based therapies were well known and generally well characterized at the time of the invention. However, use of adenoviral based therapies for the treatment of VEGF related diseases was limited to delivery of rAAVs encoding VEGF inhibitors or anti-VEGF Fab fragments.
The artisan of ordinary skill would be one having an advanced degree in biology and/or significant experience in studying adenoviral vectors or VEGF related diseases. One may have experience in clinical trials, per se, but would at least have extended knowledge regarding assaying the effects of adenoviruses when administered to a subject.
At the time the invention was made, adenoviral vectors expressing VEGF inhibitors or anti-VEGF Fab fragments, were known to be effective for treating VEGF-related disease (See Apte et al (Cell, 2019), Sec. The Vista for Multitarget, Synergistic Approaches in Clinical Pharmacotherapy). Thus, use of a rAAVs expressing VEGF inhibitors or anti-VEGF Fab fragments, for the treatment of VEGF-related diseases was taught by the prior art, or would have been predictable based on the teachings of the prior art, at the time the inventions was made. However, use of any rAAV, expressing any nucleic acid sequence (e.g. any gene or an empty rAAV), was not known to be suitable for the treatment of VEGF-related diseases. There was no evidence at the time the invention was made that an rAAV lacking a sequence which encodes a modulator of VEGF or VEGF signaling would have any effect on the symptoms or causes of a VEGF related disease. There was no known link between an rAAV per se and treatment of VEGF-related diseases. Instead, it is the VEGF inhibitors or anti-VEGF Fab fragments expressed by the rAAV which would have a therapeutic effect on a subject having a VEGF-related disease.
Example 1 of the specification discloses an rAAV comprising a nucleic acid sequence encoding anti-VEGF protein. Examples 2-17 disclose different formulations comprising the rAAV and test the thermal stability of the formulation. There are no examples drawn to use of an rAAV for the treatment of a VEGF-related disease.
In total, the specification and prior art support that rAAVs comprising VEGF inhibitors or anti-VEGF Fab fragments/proteins can be used to treat VEGF-related diseases. The scope of the claims is beyond what was known/expected based on the prior art, and taught in the instant specification.
Claims 57-58 depend from claim 56 without further defining the rAAV and thus inherit the deficiencies of claim 56.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 30-58 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 30 recites the pharmaceutical composition comprises a recombinant adeno-associated virus and a buffer… However, several more components of the pharmaceutical composition are listed after “a buffer” without any conjunction. The claim could thus be interpreted as:
the pharmaceutical composition comprises a recombinant adeno-associated virus, a buffer, an amino acid, a stabilizer, and a nonionic surfactant, with the buffer being a citrate buffer.
the pharmaceutical composition comprises a recombinant adeno-associated virus, a buffer, an amino acid, a stabilizer, or a nonionic surfactant, with the buffer being a citrate buffer.
the pharmaceutical composition comprises a recombinant adeno-associated virus and a buffer wherein the buffer comprises an amino acid, a stabilizer, and a nonionic surfactant, with the buffer being a citrate buffer.
the pharmaceutical composition comprises a recombinant adeno-associated virus and a buffer wherein the buffer comprises an amino acid, a stabilizer, or a nonionic surfactant, with the buffer being a citrate buffer.
For the purpose of compact prosecution, the claim is being interpreted as option 1 (See claim interpretation section above). Claims 31-58 depend from claim 30 or require the pharmaceutical composition of claim 30 without further defining which of the recited components are required to be part of the pharmaceutical composition of claim 30 and thus inherit the deficiencies of claim 30.
Further regarding claims 33-36: Claims 33-36 do not include a conjunction and therefore it is unclear whether the pharmaceutical composition requires all the listed concentrations or whether the claims requires any of the components to be at the listed concentrations.
Further regarding claim 44: Claim 44 recites the limitation "the antibody heavy chain", "the antibody light chain", and "the above antibody" in c) and d). There is insufficient antecedent basis for this limitation in the claim.
Further regarding claim 44: Claim 44 a) and b) recite fusion proteins comprising amino acid sequences of SEQ ID NO: 1 and 2 respectively; claim 44 c) recites an antibody comping a heavy chain variable region of SEQ ID NO: 3 and a light chain variable region of SEQ ID NO: 4; claim 44 d) recites an antibody heavy chain variable region of SEQ ID NO: 5 and an antibody light chain variable region of SEQ ID NO: 6. Claim 44 d) further recites “or an antibody or a protein comprises sequence with at least 80% identity to the above antibody or protein”. Claims 30 and 44 do not recite an antibody sequence. Claim 44 only recites sequences pertaining to the heavy and light chain variable regions.
Additionally, It is unclear whether the “above antibody or protein” can refer to any protein with at least 80% sequence identity to 44 a) or b) and any antibody having at least 80% sequence similarity to the heavy and light chain variable regions of 44 c) or d) or whether the protein or antibody has at least 80% sequence identity to only the antibody heavy and light chain variables recited in 44 d).
Further regarding claim 49 does not comprise a conjunction thus it is unclear if the pharmaceutical composition is required to be all the listed formulations or any of the listed formulations.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 48 and 49 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 48 and 49 recite “the pharmaceutical composition is an intravitreal injection formulation, a subretinal injection formulation…”. However, the claims and specification of the instant application do not disclose any requirements which distinguish an intravitreal injection formulation, a subretinal injection formulation, etc. from the pharmaceutical composition of claim 30. Thus, claims 48 and 49 do not further limit the pharmaceutical composition of claim 30.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 30-36, 38-44, and 48-53 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Marshall et al (US20220143115A1), published 05/12/2022 as evidenced by Harding et al (US9079953B2).
Marshall et al discloses a stable formulation comprising recombinant adeno-associated virus (rAAV) particles and a buffering agent, a sugar, and a salt comprising sodium citrate (See ¶0017). In some embodiments the buffering agent comprises Tris, sucrose and sodium citrate (See ¶007). In some embodiments the formulation further comprises a non-ionic surfactant such as poloxamer 188, polysorbate 20, or polysorbate 80 (See ¶007 and claim 49). In some embodiments the formulation comprises one or more stabilizers such as sugar or amino acids (See ¶454). The buffering agent of Marshall et al can comprise any of histidine, glycine, lysine, arginine, and sodium citrate (See ¶0508). The sugar in the formulation of Marshall et al can comprise sucrose, trehalose, glucose, fructose, mannose, galactose, lactose, dextrose, or any combination thereof (See ¶0518). The concentration of sodium citrate can comprise about 40 mM (See claim 43). The buffering agent is present at a concentration between 1 mM and about 50 mM… or about 40 mM (See ¶0509). The non-ionic surfactant is present in the formulation at a concentration between about 0.0005% and about 0.01% or about 0.002% (w/v) (See claims 47-48 and ¶0021-0025 and 0073). In exemplary embodiments, poloxamer 188 is present at a concentration of 0.001% (See Table 5). The formulation comprises between about 0.1% and 5% stabilizer (See ¶0151-0152). The sugar in the formulation is present at a concentration of 100 mM to about 400 mM (See ¶0520-0525). In exemplary embodiments, the formulation comprises 4% sucrose (See ¶0439 and Table 5). In certain embodiments, the pH of the formulation is about 6.0 (Se ¶0106).
The rAAV of Marshall et al comprises a capsid protein of the AAV-8 serotype (See ¶0007). In certain embodiments the AAV encodes an anti-VEGF Fab such as ranibizumab (See ¶0604). The formulation of Marshall is suitable for intravitreal administration or subretinal administration (See ¶0638). The formulation of Marshall et al can be a liquid formulation or a lyophilized formulation (See ¶0009-0010). Marshall et al further discloses the formulation is a unit dose pharmaceutical formulation which may be within ampules and vials (See ¶0566). The formulation of Marshall et al can be used in a method of treating a disease or disorder in a subject in need thereof comprising the administration of the formulation comprising rAAV particles.
Regarding claims 30-32 and 48-49: Marshall et al discloses a stable formulation comprising a rAAV, a buffering agent, a sugar (reads on stabilizer), and a non-ionic surfactant (reads on a pharmaceutical composition). The buffering agent can comprise sodium citrate, and/or arginine (reads on a citrate buffer that is a sodium citrate buffer and comprising an amino acid that is arginine). The sugar can comprise sucrose, trehalose, glucose, lactose, or galactose. The non-ionic surfactant can comprise poloxamer 188, polysorbate 20, or polysorbate 80.
Regarding claims 33-36: Following the discussion of claim 30 above, Marshall et al discloses a formulation comprising 40 mM of sodium citrate (reads on the buffer concentration is 1mM to 200mM, 10 mM to 100 mM, 20 mM to 100 mM, and 40 mM). The formulation further comprises between about 1mM and about 50mM or about 40 mM of a buffering agent which can comprise any of histidine, glycine, lysine, arginine (reads on the claimed buffer concentrations and 5 mM to 200 mM, 20 mM to 150 mM, 40 mM to 150 mM, and 40 mM of amino acids). Additionally, the formulation comprises between about 0.1% and about 5% of a stabilizer. In exemplary embodiments the formulation comprises 4% sucrose (reads on the concentration of the stabilizer is 1%-20%, 2.5-10%, 3%-10%, and 5%). The non-ionic surfactant in the formulation of Marshall et al is present at a concentration of between about 0.0005% and about 0.01% or about 0.002% (w/v). In exemplary embodiments, the formulation comprises 0.001% poloxamer (reads on 0.001% - 0.1%, 0.001% - 0.05%, 0.001%).
Regarding claims 38-41: Following the discussion of claim 30 above, Marshal discloses the pH of the formulation is about 6.0 which reads on between 5.5-8.0, 6.0-8.0, 5.5-6.5, and 6.0±0.2. Furthermore, Marshal discloses the formulation comprises about 3x109 vector genome concentration (GC/mL). Given that the unit GC/mL is vector genomes/mL, 3x109 GC/mL reads on about 1 x 107 vg/ml to 1 x 1014 vg/ml, or about 1 x 109 vg/ml to 1 x 1013 vg/ml , or about 1 x 109 to 1 x 1012 vg/ml.
Regarding claim 42 and 43: Following the discussion of claim 30 above, the capsid protein of the rAAV of Marshall et al comprises an AAV-8 serotype which reads on the rAAV virus capsid protein serotype is AAV8 or a variant thereof.
Regarding claim 44: Following the discussion of claim 30 above, Marshall et al discloses the rAAV encodes ranibizumab which is an anti-VEGF Fab (reads on a VEGF antagonist). Harding et al teaches ranibizumab has a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10 (See Fig. 1C and Col. 9, lns 8-11). SEQ ID NO: 9 of Harding et al has 100% similarity with SEQ ID NO: 3 of the instant application and SEQ ID NO: 10 of Harding et al has 100% similarity with SEQ ID NO: 4 of the instant application. Thus, the rAAV of Marshall et al, which encodes ranibizumab, comprises a coding sequence encoding a VEGF antagonist comprising an antibody heavy chain variable region sequence of SEQ ID NO: 3 of the instant application and a light chain variable region sequence of SEQ ID NO: 4 of the instant application.
Further regarding claim 48 and 49: Following the discussion of claim 30 above, the formulation of Marshall is suitable for intravitreal administration or subretinal administration.
Regarding claims 50 and 51: Following the discussion of claim 30 above, the formulation of Marshall et al can be a liquid formulation or a lyophilized (reads on freeze-dried) formulation.
Regarding claim 52 and 53: Following the discussion of claim 30 above, Marshall discloses a formulation which is a unit dose within a vial which reads on the pharmaceutical composition is stored in a unit dose container that is a vial.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 30-44, and 48-53 are rejected under 35 U.S.C. 103 as being unpatentable over Marshall et al (US20220143115A1) as evidenced by Harding et al (US9079953B2) and in view of Cotmore et al, Journal of Virology, 2010).
The teachings of Marshall et al and Harding et al are set forth above.
Marshall et al, evidenced by Harding et al anticipates claims 30-36, 38-44, and 48-53.
Regarding claim 37: Following the discussion of claim 30 above, Marshall et al discloses the pharmaceutical composition of claim 30.
Marshall et al does not disclose a pharmaceutical composition comprising MgCl2.
Cotmore et al teaches viral particles in buffers are stable at 4°C but begin to eject their viral genome when heated (See abstract). Cotmore et al further teaches addition of MgCl2 prior to increasing the temperature of the viral particles prevents conformational shift of the viral particles and thus the particles retain their genome (See abstract).
Given that Marshall et al discloses a pharmaceutical composition comprising viral particles and a buffer and Cotmore et al discloses adding MgCl2 to compositions comprising viral particles in buffer promotes retention of viral genomes at higher storage temperatures, it would have been prima facie obvious to add MgCl2 to the pharmaceutical composition of Marshall et al. One would have been motivated to add MgCl2 to the pharmaceutical composition of Marshall et al because Cotmore et al discloses addition of MgCl2 permits for storage at higher temperatures without ejection of the viral genome by the viral particles. There is a reasonable expectation of success because Cotmore et al discloses addition of MgCl2 allows viral particles stored at higher temperatures to retain their viral genome.
Claims 30-36, 38-45, and 48-53 are rejected under 35 U.S.C. 103 as being unpatentable over Marshall et al (US20220143115A1) as evidenced by Harding et al (US9079953B2) and in view of Healy et al (US10765759B2).
The teachings of Marshall et al and Harding et al are set forth above.
Marshall et al, evidenced by Harding et al anticipates claims 30-36, 38-44, and 48-53.
Regarding claim 45: Following the discussion of claims 30 and 44 above, Marshall et al discloses a formulation comprising a rAAV that encodes an anti-VEGF Fab.
Marshall et al does not disclose the anti-VEGF Fab comprises the amino acid sequence of SEQ ID NO: 7 of the instant application.
Healy et al discloses a scFv anti-VEGF antibody comprising SEQ ID NO:5 which reads on a single-chain antibody (See Fig. 18). SEQ ID NO: 5 of Healy et al has 100% similarity to SEQ ID NO: 7 of the instant application (See sequence alignment at end of office action).
Given that Marshall et al discloses an rAAV encoding an anti-VEGF Fab and Healy et al discloses a an a scFV anti-VEGF antibody comprising SEQ ID NO: 5, it would have been prima facie obvious to substitute the anti-VEGF Fab of Marshall et al with the anti-VEGF scFV of Healy et al, in the rAAV of Marshall et al. One would have expected the anti-VEGF scFV of Marshall et al to work equivocally with the anti-VEGF Fab of Marshall et al, in the rAAV of Marshall et al, because the scFV of Healy et al and the Fab of Marshall et al are both anti-VEGF antibody fragments. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Claims 30-36, 38-44, and 46-53 are rejected under 35 U.S.C. 103 as being unpatentable over Marshall et al (US20220143115A1) as evidenced by Harding et al (US9079953B2) and in view Gao et al (WO2021046245A1).
The teachings of Marshall et al and Harding et al are set forth above.
Marshall et al, evidenced by Harding et al anticipates claims 30-36, 38-44, and 48-53.
Regarding claim 46: Following the discussion of claim 1 above, Marshall et al discloses a formulation comprising a rAAV of serotype AAV-8, encoding an anti-VEGF Fab.
Marshall et al does not disclose any further components of the expression cassette which encodes the anti-VEGF Fab.
Gao et al discloses an rAAV comprising a nucleic acid, comprising in 5’ to 3’ order:
a 5’ AAV ITR;
a CMV enhancer;
a CBA promoter;
a chicken beta-actin intron;
a Kozak sequence;
an anti-VEGF agent encoded by SEQ ID NO: 1;
a rabbit beta-globin poly A signal and;
a 3’ AAV ITR
(See claim 32 and Fig. 1c). The nucleic acid in the rAAV of Gao et al thus reads on the polynucleotide expression cassette in (ii)(a)-(f) of the instant application. Additionally, the rAAV of Gao et al can have a capsid protein of serotype AAV8 (See pg. 30, lns 13-20).
Given that Marshall et al discloses a formulation comprising a rAAV of serotype AAV8 and encodes an anti-VEGF Fab (reads on a VEGF antagonist) and Gao et al discloses a rAAV of serotype AAV8 that encodes an anti-VEGF agent (reads on a VEGF antagonist), it would have been prima facie obvious to substitute the rAAV of Marshall et al with the rAAV of Gao et al in the formulation of Marshall et al. One would have expected the rAAV of Gao et al to work equivocally with the rAAV of Marshall et al in the formulation of Marshall et al because Gao et al and Marshall et al both disclose rAAVs of serotype AAV8 which encode a VEGF antagonist. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 47: Following the discussion of claims 30 and 46 above, Marshall et al discloses the pharmaceutical composition of claim 30. It would be obvious to substitute the rAAV of Gao et al for the rAAV of Marshall et al, in the pharmaceutical composition of Marshall et al (See rejection of claim 46 above). The rAAV of Gao et al comprises an expression cassette comprising the nucleotide sequence of SEQ ID NO: 2 (See pg. 24 ln 28 – pg. 26, ln. 21). The nucleotide sequence of SEQ ID NO: 2 of Gao et al shares 99.9% similarity to SEQ ID NO: 9 of the instant application and thus reads on a nucleotide sequence of SEQ ID NO: 9 (See sequence alignment at end of office action).
Claims 30-36, 38-44, and 48-55 are rejected under 35 U.S.C. 103 as being unpatentable over Marshall et al (US20220143115A1) as evidenced by Harding et al (US9079953B2) and in view of Ruiz (US20140242113A1).
The teachings of Marshall et al and Harding et al are set forth above.
Marshall et al, evidenced by Harding et al anticipates claims 30-36, 38-44, and 48-53.
Regarding claims 54 and 55: Following the discussion of claims 30, 52, and 53 above, Marshall discloses the pharmaceutical composition of claim 30. Marshall et al further discloses storing said pharmaceutical composition in a vial as a unit dose.
Marshall et al does not disclose the vial is a glass vial or storing in a pre-filled syringe.
Ruiz discloses a liquid vaccine preparation which can comprise an adenovirus, a buffer, and stabilizers (See ¶0007, 0015-0016, and 0030). The liquid vaccine preparation of Ruiz is configured into a delivery device containing a single dosage amount (reads on unit dose) such as a syringe or glass vial (See ¶0031).
Given that Marshall et al discloses a pharmaceutical composition comprising an rAAV, a buffer, and a stabilizer which is stored in a vial as a unit dose and Ruiz discloses preparations comprising adenoviruses, buffer, and stabilizers can be stored as a unit dose in a glass vial or syringe (reads on pre-filled syringe), it would have been prima facie obvious to substitute the vial of Marshall et al with the glass vial or syringe of Ruiz in the storage method of Marshall et al. One would have expected a glass vial or syringe to work equivocally with the vial of Marshall et al in the storage method of Marshall et al because Ruiz teaches glass vials and syringes can be used to store unit doses of pharmaceutical compositions comprising adenoviruses, buffer, and stabilizers. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Claims 30-36, 38-44, 48-53, and 56-58 are rejected under 35 U.S.C. 103 as being unpatentable over Marshall et al (US20220143115A1) as evidenced by Harding et al (US9079953B2) and in view of Apte et al (Cell, 2019).
The teachings of Marshall et al and Harding et al are set forth above.
Marshall et al, evidenced by Harding et al anticipates claims 30-36, 38-44, and 48-53.
Regarding claims 56-58: Marshall et al discloses a formulation which anticipates the pharmaceutical composition of claim 30 (See rejection of claim 1 above). The formulation of Marshall et al comprises a rAAV which encodes an anti-VEGF Fab, such as ranibizumab. Marshall et al further discloses the formulation can be administered to a subject in a method of treating a disease.
Marshall et al does not disclose using the formulation in a method for treating VEGF-related disease comprising ocular neovascularization disease.
Apte et al reviews VEGF signaling and disease (See abstract). Apte et al teaches VEGF has a role in the development of ocular neovascularization in diseases such as diabetic retinopathy and age-related macular degeneration (AMD) (See Sec. A conceptual Vision for VEGF in Ocular Neovascularization). Apte et al further teaches adenoviral vectors expressing VEGF inhibitors or anti-VEGF Fab fragments, are effective for treating VEGF-related disease (See Sec. The Vista for Multitarget, Synergistic Approaches in Clinical Pharmacotherapy). Additionally, ranibizumab, a humanized Fab antibody fragment targeting all isoforms of VEGF-A is approved for intravitreal delivery in the treatment of neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vascular occlusions (See Box 2).
Given that Marshall et al discloses a formulation comprising an rAAV that encodes ranibizumab and can be used to treat a disease and Apte et al teaches adenoviral vectors expressing anti-VEGF Fab antibodies are effective for treating VEGF-related disease and ranibizumab is approved for the treatment of neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vascular occlusions, it would have been prima facie obvious to use the formulation of Marshall et al to treat a VEGF disease selected from neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vascular occlusion. One would have been motivated to use the formulation of Marshall et al to treat VEGF related neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vascular occlusions because the formulation of Marshall et al comprises a rAAV which encodes ranibizumab and Apte et al teaches ranibizumab is approved for the treatment of neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vascular occlusions. There is a reasonable expectation of success because Apte et al teaches adenoviral vectors expressing anti-Fab antibodies can be used to treat VEGF related disease and the anti-VEGF Fab ranibizumab is approved for the treatment of neovascular AMD, diabetic retinopathy, diabetic macular edema, and retinal vascular occlusions.
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 30-36, 38-44, and 48-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-15, and 17-22 of copending Application No. 19/587354 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claim 30 : Claim 1 of 19/587354 is drawn to a pharmaceutical composition comprising a recombinant adeno-associated virus, wherein the pharmaceutical composition further comprise a buffer solution, an amino acid, a stabilizer, and a non-ionic surfactant, wherein the buffer solution is a citrate buffer… which reads on claim 30 of the instant application.
Regarding claims 31 and 32: Claim 1 of 19/587354 further recites, the amino acid is selected from aspartic acid, arginine, glycine, histidine, and proline, the stabilizer is selected from sucrose trehalose, mannitol, lactose, galactose, glucose, and maltose, the non-ionic surfactant is selected from poloxamer 188, polysorbate 20, polysorbate 80, HS15, and TPGS which reads on the limitations of claims 31 and 32
Regarding claim 33: Claim 2 of 19/587354 recites wherein the concentration of the buffer is from 10mM to 200 mM (overlaps with 1mM to 200mM), the concentration of the amino acid is from 10mM to 200 mM (overlaps with 5 mM to 200mM), the concentration of the stabilizer is from 1% to 20% (reads on 1% to 20 wt%), and the concentration of the surfactant is from 0.001% to 0.1wt% (reads on 0.001% to 0.1wt%). Thus, the ranges claimed in claim 2 of 19/587354 and claim 33 of the instant application overlap. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (See MPEP2144.05(I); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976): In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)).
Regarding claim 34: Claim 2 of 19/587354 further recites the concentration of the buffer is from 10mM to 100 mM (reads on 10 mM to 100 mM), the concentration of the amino acid is from 20 mM to 150 mM (overlaps with 20 mM to 1500 mM), the concentration of the stabilizer is from 2.5% to 10wt% (reads on 1% to 20 wt%), and the concentration of the surfactant is from 0.001% to 0.05wt% (reads on 0.001% to 0.05wt%) which reads on the limitations of claim 34 of the instant application.
Regarding claim 35: Claim 2 of 19/587354 further recites the concentration of the buffer is from 20mM to 40 mM (overlaps with 20mM to 100mM), the concentration of the amino acid is from 40mM to 100 mM (overlaps with 40 mM to 150mM), the concentration of the stabilizer is from 3% to 10% (reads on 3% to 10 wt%), and the concentration of the surfactant is from 0.001% to 0.05wt% (reads on 0.001% to 0.05wt%). Thus, the ranges claimed in claim 2 of 19/587354 and claim 35 of the instant application overlap. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (See MPEP2144.05(I); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976): In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)).
Regarding claim 36: Claim 3 of 19/587354 recites the concentration of the buffer is 40mM (reads on 40 mM), the concentration of the amino acid is 40mM (reads on 40 mM), the concentration of the stabilizer is 5 wt% (reads on 5 wt%), and the concentration of the surfactant is from 0.001% to 0.05wt% (reads on 0.001%).
Regarding claims 38-41: Claim 4 of 19/587354 recites the pH of the pharmaceutical composition is from 5.5 to 8 (reads on claim 38), or from 6.0 to 8.0 (reads on claim 39), or from 5.5 to 6.5 (reads on claim 40), or 6.0 ±0.2 (reads on claim 41). Additionally claim 15 of 19/587354 recites the recombinant adeno-associated virus in the pharmaceutical composition is about 1 x 107 vg/ml to 1 x 1014 vg/ml (reads on claim 38), or 1 x 109 vg/ml to 1 x 1013 vg/ml (reads on claim 39), or 1 x 109 to 1 x 1012 vg/ml (reads on claim 40).
Regarding claims 42-43: Claim 5 of 19/587354 recites the capsid protein serotype of the recombinant adeno-associated virus is an AAV8 capsid protein or a modified AAV8 capsid protein which reads on the capsid protein serotype is selected from AAV8 or a variant thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 44: Claim 6 of 19/587354 reties the rAAV comprising a coding sequence for encoding an anti-VEGF protein, and the anti-VEGF protein is a fusion protein comprising the amino acid sequence set forth in SEQ ID NO: 1. SEQ ID NO: 1 of 19/587354 shares 100% similarity with SEQ ID NO: 1 of the instant application (See alignment at end of office action). Thus, claim 6 of 19/587354 recites the limitations of claim 44.
Regarding claims 48 and 49: Claims 8 and 22 of 19/587354 recites the pharmaceutical composition is an intravitreal injection preparation, a subretinal injection preparation, an intrachoroidal injection preparation… which reads on claims 48 and 49.
Regarding claims 50 and 51: Claim 9 of 19/587354 recite, the pharmaceutical composition is a liquid preparation (reads on claim 50) or is a lyophilized preparation (reads on a freeze-dried formulation and claim 51).
Regarding claim 52: Claim 11 of 19/587354 recites the pharmaceutical composition is stored in a unit dose container which reads on claim 52.
Regarding claim 53: Claim 12 of 19/587354 recites the unit dose container is a vial or syringe which reads on claim 53.
Regarding claim 54: Claim 13 of 19/587354 recites the vial is a glass vial which reads on claim 54.
Regarding claim 55: Claim 14 of 19/587354 recites the syringe is pre-filled which reads on claim 55.
Regarding claim 56: Claim 17 of 19/587354 recites a method for treating a disease associated wit VEGF, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 1. Given that the pharmaceutical composition of claim 1 of 19/587354 anticipates the pharmaceutical composition of claim 30 of the instant application, the method of claim 17 of 19/587354 anticipates the method of claim 56.
Regarding claim 57: Claim 18 of 19/587354 recites the disease associated wit VEGF is an ocular neovascular disease which reads on claim 57.
Regarding claim 58: Claim 19 19/587354 recites the ocular neovascular disease is selected from the group consisting of age-related macular degeneration, retinal neovascularization, choroidal neovascularization… which reads on claim 58.
Claims 30-36, 38-44, 46-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-15, and 17-22 of copending Application No. 19/587354 in view of Gao et al (WO2021046245A1).
The teachings of 19/587354 are set forth above.
Claims 30-36, 38-44, and 48-58 are anticipated by 19/587354.
Regarding claims 46: Claim 21 of 19/587354 recites the recombinant adeno-associated virus comprises:
a rAAV capsid protein, wherein the capsid protein is an AAV8 capsid protein or modified AAV8 capsid protein; and (reads on (i) of claim 46)
a polynucleotide expression cassette, arranged in the 5’ to 3’ direction comprising: (reads on (ii) of claim 46)
an AAV 5’ITR; (reads on (a) of claim 46)
a CBA promoter; (reads on (b) of claim 46)
a Chi intron;
a Kozak sequence; (reads on (c) of claim 46)
a nucleic acid encoding an anti-VEGF protein, wherein the nucleic acid has a nucleotide sequence as set form in SEQ ID NO: 2;
a rabbit-globin polyadenylation signal (reads on (e) of claim 46)
an AAV 3’ ITR; (reads on (f) of claim 46).
Claim 21 of 19/587354 does not disclose the nucleic acid encoding an anti-VEGF antagonist, has a nucleotide sequence of SEQ ID NO: 8 of the instant application (i.e. (e) of claim 46).
Gao et al discloses an isolated nucleic acid encoding a VEGF receptor fusion protein (reads on an anti-VEGF protein) comprising SEQ ID NO: 1 (See claims 6, 10, and 13). SEQ ID NO: 1 of Gao et al has 100% similarity with SEQ ID NO: 8 of the instant application (See alignment at end of office action). The isolated nucleic acid of Gao et al can be encoded by an rAAV (See claim 32).
Given that 19/587354 discloses an rAAV encoding an anti-VEGF protein and Gao et al discloses a an Anti-VEGF protein comprising SEQ ID NO: 1, which can be encoded by an rAAV, it would have been prima facie obvious to substitute the anti-VEGF protein of 19/587354 with the anti-VEGF protein of Gao et al, in the rAAV of 19/587354. One would have expected the anti-VEGF protein of Gao et al to work equivocally with the anti-VEGF protein of 19/587354, in the rAAV of 19/587354, because it is an anti-VEGF protein which can be encoded by an rAAV. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARISOL A O'NEILL whose telephone number is (571)272-2490. The examiner can normally be reached Monday - Friday 7:30 - 5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
Sequence Alignments
Qy (SEQ ID NO: 1) vs. Db (SEQ ID NO: 1 of 19/587,354)
Query Match 100.0%; Score 2297; DB 1; Length 432;
Best Local Similarity 100.0%;
Matches 431; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 60
Qy 61 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 120
Qy 121 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 180
Qy 181 GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 240
Qy 241 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 300
Qy 301 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS 360
Qy 361 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH 420
Qy 421 YTQKSLSLSPG 431
|||||||||||
Db 421 YTQKSLSLSPG 431
Qy (SEQ ID NO: 8) vs. Db (SEQ ID NO: 1 of Gao et al)
Query Match 100.0%; Score 1659; Length 1659;
Best Local Similarity 100.0%;
Matches 1659; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGCTTCTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGCTTCTC 60
Qy 61 ACAGGATCTAGTTCCGGAGGTAGACCTTTCGTAGAGATGTACAGTGAAATCCCCGAAATT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ACAGGATCTAGTTCCGGAGGTAGACCTTTCGTAGAGATGTACAGTGAAATCCCCGAAATT 120
Qy 121 ATACACATGACTGAAGGAAGGGAGCTCGTCATTCCCTGCCGGGTTACGTCACCTAACATC 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ATACACATGACTGAAGGAAGGGAGCTCGTCATTCCCTGCCGGGTTACGTCACCTAACATC 180
Qy 181 ACTGTTACTTTAAAAAAGTTTCCACTTGACACTTTGATCCCTGATGGAAAACGCATAATC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ACTGTTACTTTAAAAAAGTTTCCACTTGACACTTTGATCCCTGATGGAAAACGCATAATC 240
Qy (SEQ ID NO: 9) vs. Db (SEQ ID NO: 2 of Gao et al)
Query Match 99.5%; Score 3987; Length 4011;
Best Local Similarity 99.9%;
Matches 4009; Conservative 0; Mismatches 0; Indels 2; Gaps 2;
Qy 1 CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTT 60
Qy 61 GGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACT 120
Qy 121 AGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACCAGGGTAATGGGG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACCAGGGTAATGGGG 180
Qy 181 ATCCTCTAGAACTATAGCTAGTCGACATTGATTATTGACTAGTTATTAATAGTAATCAAT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ATCCTCTAGAACTATAGCTAGTCGACATTGATTATTGACTAGTTATTAATAGTAATCAAT 240
Qy 241 TACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAA 300
Qy (SEQ ID NO: 3) vs. Db (SEQ ID NO: 9 of Harding et al)
Query Match 100.0%; Score 679; DB 1; Length 231;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVT 120
Qy 121 VSS 123
|||
Db 121 VSS 123
Qy (SEQ ID NO: 4) vs. Db (SEQ ID NO: 10 of Harding et al)
Query Match 100.0%; Score 648; DB 1; Length 214;
Best Local Similarity 100.0%;
Matches 124; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQ 124
||||
Db 121 SDEQ 124
Qy (SEQ ID NO: 7) vs. Db (SEQ ID NO: 5 of Healy et al)
Query Match 100.0%; Score 1343; Length 280;
Best Local Similarity 100.0%;
Matches 252; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MEIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MEIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVP 60
Qy 61 SRFSGSGSGAEFTLTISSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLGGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SRFSGSGSGAEFTLTISSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLGGGGGSGGG 120
Qy 121 GSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQAPGKGLEW 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQAPGKGLEW 180
Qy 181 VGFIDPDDDPYYATWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDHNSGWGLD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VGFIDPDDDPYYATWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDHNSGWGLD 240
Qy 241 IWGQGTLVTVSS 252
||||||||||||
Db 241 IWGQGTLVTVSS 252
