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
This application is a CON of PCT /CN2020/128588 filed 11/13/2020. Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on CN 201911302937.3 filed 12/17/2019, CN 202010506950. 7 filed 06/05/2020, CN 202010976582.2 filed 09/16/2020 and CN 202010974997.6 09/16/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims 5-13 and 15-25 are pending. Claims 5-11, 15 and 16 were amended. Claims 1-4 and 14 are cancelled. Claims 5-7, 12, 13, 15, 21-23 and 25 were withdrawn.
Claims 8-12, 16-20 and 24 (claims set filed 05/11/2026) are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 05/11/2026 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
The previous claim 8 objection has been withdrawn necessitated by amendment of claim 8.
The previous claims 10, 11, 17, 20 and 24 rejections under 35 U.S.C. 112(b) have been withdrawn necessitated by amendment of claims 10 and 11.
Maintained/Modified Rejections
The following rejections are maintained and/or modified taking into consideration amendment to claims filed on 05/11/2026.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 8-12, 17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Xiao (CN 109432403 on record in IDS) in view of Walker (US 8633153 B2 on record in IDS) and Xiang (JP 2019182825A) and as evidenced by Betts (Betts and Russell Bioinformatics for Geneticists, 2003, Chapter 14, 289-316).
Regarding claims 8 and 12, Xiao teaches application of transthyretin (TTR) in inhibiting angiogenesis (paragraph 0002) and ocular neovascularization (paragraph 0010). Xiao describes that ocular angiogenesis-related diseases include chondroidal neovascularization, diabetic retinopathy, diabetic macular edema, age-related macular degeneration and retinal vein occlusion (paragraph 0015). Xiao discloses pharmaceutical composition comprising TTR and pharmaceutically acceptable carrier (paragraph 0016) and the dosage form of the composition for injection (paragraph 0017). Xiao showed that administration of TTR to mammals significantly reduced ocular neovascularization in STZ-induced diabetic rat and mouse models (paragraph 0019).
Xiao does not teach (1) TTR to consist of sequence of SEQ ID NO: 1 and (2) the eye drops to comprise diclofenac.
Walker teaches TTR or TTR variant which can be used as a fusion partner with a biologically active agent to increase the half-life of the biologically active agent (column 2, lines 14-21). Walker provides the sequence of human transthyretin with SEQ ID NO: 1 (column 7, lines 56-62) which is 100% identical to instant SEQ ID NO:1 and describes cloning and expression of human TTR in Escherichia coli and purification (Example 1, 6 and 7, columns 16, 21 and 22). Walker describes pharmaceutical compositions comprising TTR for administration by injection or for oral, transdermal and other forms of administration including intraocular (column 14, lines 21-26).
Xiang teaches ophthalmic composition comprising hyaluronic acid which suppresses the decrease in viscosity (Abstract). The ophthalmic composition in Xiang teaching is prepared in the form of eye drops (paragraph 0038). Xiang mentions that composition can include different pharmacologically or physiologically active ingredients and describes different ingredients (paragraph 0034). In particular, Xiang discloses that the composition comprises anti-inflammatory agents, one of which is diclofenac acid or a salt thereof, e.g. diclofenac sodium (paragraph 0026).
First, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine teaching of Xiao and Walker and use TTR with the sequence identical to instant SEQ ID NO:1 and method of its purification as described by Walker for the pharmaceutical compositions for treatment of ocular angiogenesis-related diseases as described by Xiao. One would have been motivated to make this combination since Walker described cloning, expression and purification of human TTR and methods of its modification. A skilled artisan would have reasonably expected success in this combination because Xiao and Walker teach pharmaceutical compositions comprising TTR.
Second, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow guidance of Xiang and include diclofenac sodium to the composition of TTR based on Xiao and Walker teachings and use it as eye drops. One would have been motivated to do that since Xiang teaches that diclofenac is an anti-inflammatory agent and hence its presence in the composition can prevent possible complications during treatment of eye-related diseases described by Xiao. A skilled artisan would have reasonably expected success in this combination since Xiao provides composition for treatment of eye-related diseases, Walker teaches composition that can be applied for intraocular administration and Xiang teaches ophthalmic composition in the form of eye drops.
Third, Xiao, Walker and Xiang teach the claimed structure of eye drops composition comprising transthyretin consisting of SEQ ID NO:1 and diclofenac as described above. The limitation for the eye drops to be capable of penetrating the corneal barrier for reaching the vitreous body and fundus is interpreted as the property of the claimed structure and since the prior art teaches the same structure, that structure will have the same properties and would be capable to enter the vitreous body and fundus oculi through the corneal barrier. MPEP 2112.01 states: "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present." Therefore, the eye drops composition of Xiao, Walker and Xiang teachings will necessarily have the same property of being capable of penetrating the corneal barrier for reaching the vitreous body and fundus.
Lastly, the recitation "treat ocular diseases associated with retinal neovascularization" is considered the recitation of "intended use" since the claims are directed to a product and not a method of use. The intended use is given weight to the extent that it imparts a structural limitation and the prior art needs to be capable of performing the intended use. See MPEP 2111.02. In instance case, Xiao teaches a TTR composition for treatment of ocular angiogenesis-related diseases and shows that treatment with TTR results in reduction of ocular neovascularization in animal models. Thus, the prior art would be capable of treating ocular diseases associated with retinal neovascularization.
Thus, Xiao, Walker and Xiang teachings render claims 8 and 12 obvious.
Regarding claim 9 and 10, Walker teaches variants of TTR with cysteine residue at position 10 substituted with alanine (column 77, claims 1 and 2). This substitution is a hydrophobic modification as evidenced by Betts (p. 298, 4th paragraph) and hence it reads on limitation of claim 9. Walker describes expression of TTR and its mutants in E. coli followed by purification in Examples 6 and 7 (columns 21-23) that covers the 7th alternative limitation of claim 10. Walker showed that mutation of cysteine at position 10 to alanine did not have a significant impact on oligomeric structure in Example 12 (column 24, lines 66-67 and column 25, line 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow guidance of Walker on expression of TTR in microbial cells and purification and modification of TTR by introducing hydrophobic modification at cysteine at position 10. One would have been motivated to do that with reasonably expected success since Walker provided instructions for expression and purification of TTR and showed that hydrophobic substitution at position 10 does not impact the oligomeric structure of TTR indicating that different hydrophobic modifications can be applied to cysteine at position 10 without affecting TTR function. Thus, Xiao, Walker and Xiang teachings as evidenced by Betts render claims 9 and 10 obvious.
Regarding claims 11, 17 and 20, Xiang teaches ophthalmic compositions comprising hyaluronic acid or a salt thereof (Abstract). Xiang mentions that hyaluronic acid is often used in the ophthalmic composition especially in eye drops. Xiang describes that hyaluronic acid binds to fibronectin in ocular epithelial cells to promote their adhesion and growth thereby promoting healing of corneal wounds. Additionally, hyaluronic acid has the ability to retain water and hence prevents dry eyes (paragraph 0002). Xiang describes that since hyaluronic acid or a salt thereof has a high viscosity, an ophthalmic composition containing hyaluronic acid or a salt thereof has a long contact time with the corneal and conjunctival epithelium, and can fully exert its pharmacological action (paragraph 0003). Xiang discloses the ophthalmic compositions with hyaluronic acid having average molecular weight of 300,000 to 3,900,000 (paragraph 0006) that reads on claim 17 limitation for hyaluronic acid. Xiang describes the concentration of hyaluronic acid in the composition of more than 0.1 w/v % and less than 10 w/v % (paragraph 0016) that reads on limitation for hyaluronic acid in claim 20.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow guidance of Xiang and include hyaluronic acid of molecular weight of 300,000 to 3,900,000 and at concentration from 0.1 to 5 w/v % to the composition of TTR based on Xiao and Walker teachings. One would have been motivated to make this combination with reasonably expected success since Xiang teaches that hyaluronic acid promotes corneal healing and prevents dry eyes and due to its high viscosity provides longer contact with corneal and hence will increase therapeutic effect of TTR composition. Thus, Xiao, Walker and Xiang teachings render claims 11, 17 and 20 obvious.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Xiao (CN 109432403 on record in IDS) in view of Walker (US 8633153 B2 on record in IDS) and Xiang (JP 2019182825A) and as evidenced by Betts (Betts and Russell Bioinformatics for Geneticists, 2003, Chapter 14, 289-316) as applied to claims 8 and 9 above, and further in view of Fernyhough (US 20170027957 Al).
The teachings of Xiao, Walker and Xiang have been set forth above.
Xiao, Walker and Xiang do not teach TTR modification with a long chain hydrophobic fragment such as n-dodecane at cysteine 10.
Fernyhough teaches different classes of chemical compounds with various mechanism of action that can be used as penetration enhancers (paragraph 0099). Fernyhough discloses alkanones among those compounds which include instant n-dodecane: "Another class of penetration enhancers are alkanones, such as N-heptane, N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane, N-tetradecane and N-hexadecane." (paragraph 0100).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute hydrophobic modification at Cys10 in TTR in Walker teaching with N-dodecane from Fernyhough teaching in composition comprising TTR based on Xiao, Walker and Xiang teachings. One would have been motivated to make this substitution since Fernyhough teaches that n-dodecane is a penetration enhancer and hence it can promote penetration of TTR or TTR fused with biological agent into eye and Walker showed that hydrophobic modification at position 10 did not impact the oligomeric structure of TTR. A skilled artisan would have reasonably expected success in this combination since Xiao and Walker teach TTR in the pharmaceutical compositions and Fernyhough describes component that can increase efficiency of TTR delivery. Thus, Fernyhough teaching in combination with Xiao, Walker and Xiang teachings as evidenced by Betts renders claim 16 obvious.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Xiao (CN 109432403 on record in IDS) in view of Walker (US 8633153 B2 on record in IDS) and Xiang (JP 2019182825A) as applied to claims 8 and 12 above, and further in view of Mingatto (Mingatto et al. Arch. Biochem. Biophys., 1996, 334, 303-308).
The teachings of Xiao, Walker and Xiang have been set forth above.
Xiao, Walker and Xiang do not teach the diclofenac or diclofenac content of 5-20 μmol/L or 10 μmol/L.
Regarding claim 18 and 19, Mingatto teaches evaluation of the interference of nonsteroidal anti-inflammatory drugs, including diclofenac, on respiration of rat kidney mitochondria and ATP synthesis (Abstract). Mingatto mentions that kidney is an important target for non-steroidal anti-inflammatory drugs toxicity (p. 303, right column, 2nd paragraph). Mingatto discloses that diclofenac affected the mitochondrial respiration at 30-100 μM at stage 4 (uncoupled state) and depressed respiration at 17- 100 μM at stage 3 (active respiration) (p. 306, left column, last paragraph and right column, 1st paragraph). Diclofenac inhibited ATP synthesis with IC50 of 0.1 mM (p. 306, left column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow teaching of Mingatto and use diclofenac at less than 17 μM in ophthalmic composition based on Xiao, Walker and Xiang teachings. One would have been motivated to do that since Mingatto showed inhibition of kidney mitochondria by diclofenac at 17-100 μM and usage of concentrations of less than 17 μM (17 μmol/L) will prevent kidney toxicity. A skilled artisan would have reasonably expected success in this combination since Xiao, Walker and Xiang describe pharmaceutical compositions capable of being administrated to eyes, Xiang teaches diclofenac in the eye drops composition and Mingatto provides safe concentration of diclofenac for treatment. Thus, Mingatto teaching in combination with Xiao, Walker and Xiang teachings renders claims 18 and 19 obvious.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Xiao (CN 109432403 on record in IDS) in view of Walker (US 8633153 B2 on record in IDS) and Xiang (JP 2019182825A) as applied to claims 8 and 10 above, and further in view of Napoli (US 20040106546 Al).
The teachings of Xiao, Walker and Xiang have been set forth above.
Xiao, Walker and Xiang do not teach the Tween 80 content in eye drops of 5%. Although Walker teaches solubilizing agents in the pharmaceutical composition such as Tween 80, Walker does not provide Tween 80 concentration.
Napoli teaches ophthalmic formulations comprising cyclosporin, hyaluronic acid and Tween 80 (polysorbate 80) (Abstract). Napoli discloses that formulation is administered into eye in the form of eye drops (paragraph 0045). Napoli provides composition of different formulations in Table 1 with the concentration of Tween 80 from 0.05 to 20% (paragraph 0048) and mentions that in the preferred embodiment the concentration of Tween 80 in formulation is 5% (paragraph 0041). Napoli describes results of multiple tests performed with formulation # 3 containing 5% Tween 80 in comparison with another formulation comprising cyclosporin, i.e. CYCLOIL and reported that formulation #3 provided better bioavailability and is better tolerated than CYCLOIL (paragraph 0114).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow teaching of Napoli and use 5% Tween 80 as solubilizer as described by Napoli in ophthalmic composition based on Xiao, Walker and Xiang teachings. One would have been motivated to do that since Napoli showed improved tolerance and compound bioavailability of formulation containing 5% Tween 80. A skilled artisan would have reasonably expected success in this combination since Xiao and Walker teach TTR in the pharmaceutical compositions, Xiang and Napoli described ingredients of eye drop compositions and all Xiao, Walker, Xiang and Napoli describe pharmaceutical compositions capable of being administrated to eyes. Thus, Napoli teaching in combination with Xiao, Walker and Xiang teachings renders claim 24 obvious.
Response to Arguments
Applicant's arguments filed 05/11/2026 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 11-14 of the Remarks) that “the actual technical problem solved by amended claim 8 is to provide eye drops capable of treating ocular diseases associated with retinal neovascularization.” Applicant adds that “eye drops” is not merely an intended use limitation and impart structural meaning to the claimed invention. Xiao teaches intravitreal injection of TTR for treatment of retinal neovascularization and Walker teaches injection-based ocular administration and not as eye drops and hence Xiao and Walker teach away from the eye drops. Applicant further argues that Xiao and Xiang do not teach SEQ ID NO:1 for TTR, composition and eye drops comprising TTR and diclofenac. Applicant argues that none of the references provides any teaching or suggestion that eye drops comprising TTR could exert a therapeutic effect on retinal disease and one of ordinary skill in the art would not have motivation and would not have reasonably expected the combination of TTR from Xiao and Walker with diclofenac-containing eye drops of Xiang to successfully provide therapeutic benefits to retinal neovascularization. Applicant indicates that “the present inventors unexpectedly discovered that TTR can penetrate ocular barriers following topical administration and exert therapeutic effects against ocular diseases associated with retinal neovascularization.”. These arguments are not persuasive because:
First, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, rejection of claim 8 is based on combination of prior art of Xiao, Walker and Xiang. Xiao teaches TTR for treatment of ocular neovascularization (paragraph 0019), Walker provides sequence for TTR (column 7, lines 56-62) and mentions that TTR can be used for ocular administration (column 12, lines 21-26) and Xiang teaches ophthalmic composition in the form of eye drops that includes diclofenac as anti-inflammatory agent (paragraphs 0026, 0038) providing motivation to combine TTR and diclofenac in an eye drop composition to prevent complications during treatment of eye-related disease and since ocular neovascularization is taught to be caused by inflammation as evidenced by Mesquida (Mesquida et al. Seminars in lmmunopathology, 2019, 41, 427-445) and hence one would expect diclofenac, an anti-inflammatory agent, to treat retinal neovascularization. Therefore, Xiao, Walker and Xiang compositions can be combined with reasonable expectation of therapeutic effect because these compositions are used for the same purpose of treating ocular diseases including inflammation and the eye drops is a common form of application for eye diseases.
Second, the penetration of ocular barriers by TTR following topical administration and exertion of therapeutic effects against ocular diseases associated with retinal neovascularization recognized by the Applicant does not make the combination of prior art non-obvious because the prior art does not need to point out all advantages if there is a motivation to combine the prior art. MPEP 2145: "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." In instant case, combination of prior art is obvious and TTR and diclofenac can be used for the same conditions as described above providing motivation for their combination. Additionally, Xiao teaches a TTR composition for treatment of ocular angiogenesis-related diseases and shows that treatment with TTR results in reduction of ocular neovascularization in animal models. Therefore, the eye drop composition of TTR and diclofenac is expected to have the same advantage of penetration of ocular barriers and exertion of therapeutic effects against ocular diseases associated with retinal neovascularization
Last, “penetration of ocular barriers by TTR for reaching the vitreous body following topical administration” is interpreted as functional property of the structure, i.e. a composition comprising transthyretin consisting of SEQ ID NO:1 and diclofenac, which is obvious over combination of prior art of Xiao, Walker and Xiang as described in the rejection above. Since the prior art teaches the same structure, the eye drops composition of Xiao, Walker and Xiang teachings will necessarily have the same property of penetration of ocular barriers by TTR following topical administration. “Exertion of therapeutic effects against ocular diseases associated with retinal neovascularization” is interpreted as intended use of the structure as described in the rejection above. Since prior art teaches the same structure and Xiao teaches TTR for treatment of ocular neovascularization, the prior art would be expected to be capable of providing therapeutic effect against ocular diseases associated with retinal neovascularization.
Therefore, the 35 U.S.C. 103 rejection is maintained and modified necessitated by amendment of claims
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIOUBOV G KOROTCHKINA whose telephone number is (571)270-0911. The examiner can normally be reached Monday-Friday: 8:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila G Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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