DETAILED ACTION
This action is in reply to papers filed 1/23/2026.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240108669A1, Published 10/6/2020.
Election/Restrictions
Applicant’s election of Group III, claims 67, 187-188, 190, 195-199 and 213-235 in the reply filed on 1/23/2026. is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1, 3-4, 6-10, 12, 54-55, 57 and 200-212 are withdrawn as being drawn to non-elected inventions. Accordingly, claims 1, 3-4, 6-10, 12, 54-55, 57, 67, 187-188, 190, 195-212 and 213-235 pending with claims 67, 187-188, 190, 195-199 and 213-235 examined herein.
Claim Rejections - 35 USC § 112
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 87, 188, 195-196, 216 and 232-233 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.
Claims 87 and 188 both recite “the pH’ in line 1. There is insufficient antecedent basis for this limitation in the claims and the claims in which they depend from.
Claims 195 and 196 recite, inter alia, “..the vector genome concentration” or “the VGC” in line 1. There is insufficient antecedent basis for this limitation in the claims and the claims in which they depend from
Claims 216 and 232 both recite the limitation "comprising both said salt excipient and said buffer agent" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Note that independent claim 213 recited the composition comprise a salt excipient or a buffer agent. Claim 213 did not claim an embodiment in which both the salt excipient and the buffer agent were comprised in the composition. Claim 233 is included as it depends from claim 232 and further limits the salt excipient or a buffer agent..
Appropriate correction is requested.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 67, 187-188, 190, 195-199 and 213-235 are rejected under 35 U.S.C. 103 as being unpatentable over Tretiakova et al. (PgPub US20190381194A1, Filed 4/14/2017), Wu et al. (PgPub US20080107631A1, Published 5/8/2008), Laurie et al. (PgPub US20170322227A1, Filed 6/1/2017), Popov et al. (PgPub US20150125539A1, Filed 11/2/2013) and Adamson et al. (WO2010136492A2, Published 12/2/2010).
Claim interpretation: Claim 235 recites, inter alia, “…said composition is effective in treating a retinal disease in an eye of a human subject upon administration to said eye.” This is an intended use of the claimed composition and does not limit the scope of the claimed composition because it does not impose a structural distinction.
Tretiakova et al. teach a recombinant adeno-associated virus (rAAV) having an AAV8 capsid (as in claim 213) which is suitable for subretinal (as in claim 199) and/or intra-retinal injection (Abstract), wherein the rAAV comprises a vector genome packaged within the capsid, said vector genome comprising: (a) an AAV2 inverted terminal repeat (ITR) (as in claim 213) (Pg. 15, para. 169); (b) a coding sequence for an anti-human vascular endothelial growth factor (VEGF) antigen binding antibody fragment (Fab) having an exogenous leader sequence, a heavy immunoglobulin chain, a linker, and a light immunoglobulin chain having an exogenous leader sequence, wherein the coding sequence is operably linked to regulatory elements which direct expression of the anti-VEGF Fab in the eye (Abstract); (c) a CB7 promoter, a hybrid of a cytomegalovirus immediate-early enhancer and the chicken β-actin promoter(as in claim 213) (Pg. 2, para. 16), wherein the transcription from this promoter is enhanced by the presence of the chicken β-actin intron (as in claim 213) and the polyadenylation signal for the expression cassette is from the rabbit β-globin gene(as in claim 213), wherein said promoter directs the expression of the heavy and light immunoglobulin chains of the anti-VEGF Fab (see Tretiakova at claim 1), wherein the nucleic acid sequences coding for the heavy and light chains of anti-VEGF Fab are separated by a self-cleaving furin (F)/F2A linker (as in claim 213); and (d) an AAV2 ITR (Pg. 15, para. 169); wherein the rAAV is suspended in an liquid (as in claim 197) solution (~pharmaceutical composition as in claim 213) comprising buffered saline (as in claim 213) with a surfactant (as in claim 213) and/or other excipients (Pg. 8,para. 72). Tretiakova teaches the buffered saline typically contains a physiologically compatible salt or mixture of salts, e.g. phosphate buffered saline, sodium chloride, or a mixture thereof (as in claim 216 and claim 232) (Pg. 8,para. 72). Tretiakova teaches the surfactant is Poloxamer 188 a concentration of 0.001% Poloxamer 188, pH 7.3 (as in claim 67, in-part, claim 222 and claim 226f) (Pg. 8, para. 74). Tretiakova teaches the pH may be in the range of 6.5 to 8, or 7.2 to 7.6 (as in claim 187, claim 188, claim 223 and claim 224). Tretiakova teaches the osmolality is less than 400 mOSM/kg H2O (as in claim 225) (Table on Pg. 34). In one embodiment, Tretiakova teaches the rAAV8.aVEGF formulation is a suspension containing at least 1×1011 genome copies (GC)/mL (as in claim 195, claim 196 and claim 227) in an injection volume ranging from about 0.1 mL to about 0.5 mL, preferably in 0.1 to 0.15 mL (100-150 μl) (as in claim 229, claim 230 and claim 231) (Pg. 11, para. 93).
Tretiakova teaches the heavy chain amino acid sequence and the light chain amino acid sequence are engineered to have an exogenous leader sequence to each have a leader sequence. Tretiakova teaches the leader sequence is SEQ ID NO: 33(Pg. 4,para. 31). The alignment between SEQ ID NO: 52 (Qy, query) and SEQ ID NO: 33 taught by Tretiakova et al. (Db, database) is provided below. Note that SEQ ID NO: 33 Tretiakova n is 100% identical to SEQ ID NO: 52 (as in claim 228)..
RESULT 32
US-16-093-420-33
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
Sequence 33, US/16093420
Publication No. US20190381194A1
Query Match 100.0%; Score 90; Length 513;
Best Local Similarity 100.0%;
Matches 20; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MYRMQLLLLIALSLALVTNS 20
||||||||||||||||||||
Db 1 MYRMQLLLLIALSLALVTNS 20
However, Tretiakova et al. fails to teach the pharmaceutical composition comprises a sugar (as further in claim 213).
Before the effective filing date of the claimed invention, Wu et al. teach that there is a need for improved, storage stable (as in claim 235) viral formulations, and methods for the production thereof, for use in gene therapy (Abstract; Pg. 1, para. 10). In one embodiment, the viral formulation is a freeze dried composition (as in claim 198) comprising, inter alia, pharmaceutical excipients that serve as a cryoprotectants (Pg. 1, para. 14). In a particular embodiment, Wu teaches the non-reducing sugar is sucrose (as in claim 213, claim 215 and claim 220) in a concentration of from about 2% to about 10% (w/v) (as in claim 220, claim 221 and claim 226e) (Pg. 1, para. 14-15).
And although Tretiakova et al. teach salt a excipient and a buffer agent, neither Tretiakova nor Wu teach the salt excipient comprises potassium chloride and sodium chloride and the buffer agent is a phosphate buffer (as further in claim 217).
Before the effective filing date of the claimed invention, Laurie teaches a sterile, aqueous pharmaceutical composition for topical administration to an ocular surface (Pg. 3, para. 34). Laurie teaches the pharmaceutical a phosphate buffer (as in claim 217 and claim 233) saline and water (as in claim 226g), wherein the buffer has the following comprises NaCl, KCl (as in claim 217 and claim 233), Na2HPO4 and KH2PO4. Laurie teaches the concentration of each component to be 137 mmol/L (~about 100 mmol/L) , 2.7 mmol/L, 10 mmol/L (~about 8.10 mmol/L), and 1 mmol/L (~about 1.47 mmol/L), respectively (as in claim 219 and claim 226,in-part, claim 232 and claim 233) (Pg. 11, para. 151).
However, none of the aforementioned references teach an ionic strength of the pharmaceutical composition (as in claim 218 and 234).
Before the effective filing date of the claimed invention, Popov et al. teach compositions and methods for ophthalmic applications (Abstract). Popov teaches that it is appreciated in the art that the ionic strength of a formulation comprising particles may affect the polydispersity of the particles (Pg.36,para. 286). Continuing, Popov teaches the ionic strength of a formulation comprising particles may also affect the colloidal stability of the particles. For example, a relatively high ionic strength of a formulation may cause the particles of the formulation to coagulate and therefore may destabilize the formulation (Pg. Pg. 36 ,para. 287). Popov adds that the ionic strength of a formulation may be controlled (e.g., increased) through a variety of means, such as the addition of one or more ionic tonicity agents (e.g., a salt such as NaCl) to the formulation (Pg. 36-37,para. 288). In certain embodiments, the ionic strength of a formulation described is greater than or equal to about 0.01 M (as in claim 218 and claim 234) (Pg. 37,para. 290).
And although Tretiakova et al. teach a nucleic acid encoding the heavy and light immunoglobulin chains of the anti-VEGF Fab, neither Tretiakova et al. nor any of the aforementioned references teach the heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 (as further in claim 67).
Before the effective filing date of the claimed invention, Adamson et al. taught antigen-binding proteins which bind to VEGF or a VEGF receptor (Abstract). The alignment between SEQ ID NO: 2 (Qy, query) and the anti-VEGF heavy chain sequence taught by Adamson et al. (Db, database) is provided below. Note the sequence taught by Adamson is 100% identical to SEQ ID NO: 2 (as further in claim 67c, as in claim 190, as in claim 214).
RESULT 1
AYN12798
(NOTE: this sequence has 110 duplicates in the database searched.
See complete list at the end of this report)
ID AYN12798 standard; protein; 231 AA.
XX
AC AYN12798;
XX
DT 17-FEB-2011 (first entry)
XX
DE Humanized anti-VEGF antibody (ranibizumab) heavy chain, SEQ ID 39 #2.
XX
KW VEGF ligand; age related macular degeneration; antibody therapy;
KW antiinflammatory; diabetic macular edema; diabetic retinopathy;
KW heavy chain; humanized antibody; ocular disease; ophthalmological;
KW prophylactic to disease; ranibizumab; retinal venous occlusion;
KW therapeutic; uveitis; vascular disease;
KW vascular endothelial growth factor; vasotropic.
XX
OS Homo sapiens.
OS Synthetic.
OS Unidentified.
XX
CC PN WO2010136492-A2.
XX
CC PD 02-DEC-2010.
XX
CC PF 26-MAY-2010; 2010WO-EP057246.
XX
PR 28-MAY-2009; 2009US-0181887P.
XX
CC PA (GLAX ) GLAXO GROUP LTD.
XX
CC PI Adamson P, Ertl PF, Germaschewski V, Gough GW, Steward M;
XX
The present sequence is a humanized anti-VEGF antibody (ranibizumab) heavy chain sequence used in the therapeutic methods of the invention.
Alignment
Query Match 100.0%; Score 1241; Length 231;
Best Local Similarity 100.0%;
Matches 231; 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 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL 231
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL 231
The alignment between SEQ ID NO: 1 (Qy, query) and the anti-VEGF light chain sequence taught by Adamson et al. (Db, database) is provided below. Note the sequence taught by Adamson is 100% identical to SEQ ID NO: 1 (as further in claim 67c, as in claim 190, as in claim 214).
AYN12640
ID AYN12640 standard; protein; 214 AA.
XX
AC AYN12640;
XX
DT 17-FEB-2011 (first entry)
XX
DE Humanized anti-VEGF antibody (ranibizumab) light chain, SEQ ID 40.
XX
KW VEGF ligand; age related macular degeneration; antibody therapy;
KW antiinflammatory; diabetic macular edema; diabetic retinopathy;
KW humanized antibody; light chain; ocular disease; ophthalmological;
KW prophylactic to disease; ranibizumab; retinal venous occlusion;
KW therapeutic; uveitis; vascular disease;
KW vascular endothelial growth factor; vasotropic.
XX
OS Homo sapiens.
OS Synthetic.
OS Unidentified.
XX
CC PN WO2010136492-A2.
XX
CC PD 02-DEC-2010.
XX
CC PF 26-MAY-2010; 2010WO-EP057246.
XX
PR 28-MAY-2009; 2009US-0181887P.
XX
CC PA (GLAX ) GLAXO GROUP LTD.
XX
CC PI Adamson P, Ertl PF, Germaschewski V, Gough GW, Steward M;
The present sequence is a humanized anti-VEGF antibody (ranibizumab) light chain sequence used inthe therapeutic methods of the invention.
ALIGNMENT:
Query Match 100.0%; Score 1114; Length 214;
Best Local Similarity 100.0%;
Matches 214; 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 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Tretiakova et al., wherein Tretiakova teaches a rAAV vector having an AAV8 capsid which is suitable for subretinal injection, wherein the rAAV comprises a vector genome packaged within the capsid, said vector genome comprising: (a) an AAV2 inverted terminal repeat (ITR) ; (b) a coding sequence for an anti-human vascular endothelial growth factor (VEGF) antigen binding antibody fragment (Fab) having an exogenous leader sequence, a heavy immunoglobulin chain, a linker, and a light immunoglobulin chain having an exogenous leader sequence, wherein the coding sequence is operably linked to regulatory elements which direct expression of the anti-VEGF Fab in the eye; (c) a CB7 promoter, wherein the coding sequences for the heavy and light chains of anti-VEGF Fab are separated by a self-cleaving furin (F)/F2A linker and (d) an AAV2 ITR, with the teachings of Wu et al., wherein Wu teaches sucrose is a cryoprotect that aids in the storage stability of formulations comprising viral vectors when freeze dried, with a reasonable expectation of arriving at the claimed invention. It would have been prima facie obvious to include sucrose in the composition of Treitiakova for the purposes of protecting the rAAV of Treitiakova when freeze-dried for later use.
Moreover, the skilled artisan would have found it prima facie obvious to substitute the generic salt excipient and buffer, taught in Treitiakova et al., for the aqueous pharmaceutical composition comprising a phosphate buffer saline comprising NaCl, KCl, Na2HPO4 and KH2PO4 of Laurie et al. because Laurie teaches such a formulation is suitable for topical administration to an ocular surface. Thus, when taken with Treitkova’ s intended use of a subretinal injection, the modification would have been prima facie obvious. Furthermore, given the teachings of Popov et al., the skilled artisan would have found it prima facie obvious to optimize the composition to adjust for ionic strength because Popov teaches the ionic strength of a formulation comprising particles may also affect the colloidal stability of the particles.
Finally, one of ordinary skill in the art would have found it prima facie obvious to use the amino acids of the heavy and light chain of the anti-VEGF antigen binding Fragment because Adamson teaches their use in ocular therapy.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
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