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 .
Detailed Action
The Amendments and Remarks filed 5/20/26 in response to the Office Action of 11/20/25 are acknowledged and have been entered.
Claims 20-22 have been added by Applicant.
Claims 1-22 are pending.
Claims 6-11, 13, 16, and 17 have been amended by Applicant.
Claims 1-22 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Withdrawn
The rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1-3, 7, 9-11, and 13-18 remain rejected and claims 20-22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834).
Ni et al teaches a method of producing synergistic and enhanced efficacy in treating a disease in a subject comprising treating the disease with an antibody-drug synergism (ADS) compound comprising an antibody that blocks a first target in the subject connected via a hydrolysable linker to a small molecule drug that blocks the first target or a second target in the subject ([0004], in particular). Ni et al further teaches said method wherein the disease is an ocular disease ([0005], in particular) and wherein the ADS is delivered to the eye and the linker hydrolyzes in vitreous humor and ocular tissue ([0033], in particular). At [0029] and [0035], Ni et al further teaches said method wherein the disease is age-related macular degeneration (AMD) and wherein the treatment is for choroidal neovascularization (CNV). Ni et al further teaches said method wherein the linker is hydrolyzed with a half-life of 1-24 hours ([0013], in particular). Ni et al further teaches ADS where the antibody is bevacizumab and the small molecule drug is slowly released from the ADS and maintains an effective concentration before the parent ADS is cleared ([0037], in particular), which is a “controlled release fashion.” Ni et al further teaches said method wherein the ADS is PEGylated ([0017], in particular). Ni et al further teaches said method wherein the linker can be esters, amides, carbamates, carbonates, imines, ethers, or phosphates ([0033], in particular).
Ni et al does not specifically teach said method wherein the small molecule drug is dexamethasone. However, these deficiencies are made up in the teachings of Liu et al.
Liu et al teaches choroidal neovascularization (CNV) is the main cause of vision impairment in age-related macular degeneration (AMD) that can be treated by targeting VEGF with dexamethasone and bevacizumab (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method to prevent vision impairment in a subject with AMD comprising the method of Ni et al to treat CMV in a subject with AMD wherein the Antibody-Drug Synergism (ADS) compound of Ni et al comprises bevacizumab of Ni et al linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al “in a controlled release fashion”) to dexamethasone of Liu et al as the small molecule inhibitor of the ADS because Ni et al teaches ADS synergistically treat ocular diseases, such as AMD, by administering a therapeutic antibody linked via a linker that hydrolyzes in vitreous humor and ocular tissue to a therapeutic small molecule that targets the disease and Liu et al teaches SNV is the main cause of vision impairment in AMD that can be treated by targeting VEGF with dexamethasone and bevacizumab (Abstract, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. This is also an example of a simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant indicates the skilled artisan would not be motivated with an expectation of success to combined the cited references wherein nanoparticles of Liu are replaced with a linker between bevacizumab and dexamethasone. Applicant further argues the rejection should be withdrawn because Liu teaches electrostatic conjugation of bevacizumab to nanoparticles was better than chemical conjugation of bevacizumab. Applicant further cites [00030] of the instant specification and indicates the rejection should be withdrawn because claimed compounds can increase the effectiveness of treatment of ocular disease providing advantages including (1) inhibiting more than one key disease mechanism with a single drug molecule and a single injection, (2) increasing effectiveness on retinal fluid removal than either single mechanism alone can achieve, (3) reducing frequency of development of resistance to a monotherapy, (4) novel route for sustained delivery of a small molecule drug to the vitreous, and (5) reducing adverse effects due to frequent intravitreal injections. Applicant further cites compound I and compound II as providing selective and controlled hydrolysis in vitreous humor.
The amendments to the claims and the arguments found in the Reply of 5/20/26 have been carefully considered, but are not deemed persuasive. In regards to the indication the skilled artisan would not be motivated with an expectation of success to combined the cited references wherein nanoparticles of Liu are replaced with a linker between bevacizumab and dexamethasone, the rejection is not based on replacing nanoparticles of Liu with a linker between bevacizumab and dexamethasone. Rather, the rejection is based on an Antibody-Drug Synergism (ADS) compound of Ni et al comprising bevacizumab of Ni et al linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al) to dexamethasone of Liu et al as the small molecule inhibitor drug of the ADS because Ni et al teaches ADS synergistically treat ocular diseases, such as AMD, by administering a therapeutic antibody linked via a linker that hydrolyzes in vitreous humor and ocular tissue to a therapeutic small molecule that targets the disease and Liu et al teaches SNV is the main cause of vision impairment in AMD that can be treated by targeting VEGF with dexamethasone and bevacizumab (Abstract, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. This is also an example of a simple substitution of one known element for another to obtain predictable results.
In regards to the argument that the rejection should be withdrawn because Liu teaches electrostatic conjugation of bevacizumab to nanoparticles was better than chemical conjugation of bevacizumab, the examiner disagrees. The rejection is not based on conjugating anything to nanoparticles.
In regards to citation of [00030] of the instant specification and indication the rejection should be withdrawn because claimed compounds can increase the effectiveness of treatment of ocular disease providing advantages including (1) inhibiting more than one key disease mechanism with a single drug molecule and a single injection, (2) increasing effectiveness on retinal fluid removal than either single mechanism alone can achieve, (3) reducing frequency of development of resistance to a monotherapy, (4) novel route for sustained delivery of a small molecule drug to the vitreous, and (5) reducing adverse effects due to frequent intravitreal injections, the examiner disagrees. Such advantages are not limited to ADS of Ni et al wherein dexamethasone is the drug of the ADS of Ni et al. Further, such advantages are not limited to ADS of Ni et al wherein the drug of the ADS of Ni et al is a small molecule drug that is an adrenergic receptor alpha agonist or an NSAID. Rather, Antibody-Drug Synergism (ADS) compounds of Ni et al provide all such advantages. See comparison with closes prior at MPEP 716.02(e).
In regards to the citation of compound I and compound II as providing selective and controlled hydrolysis in vitreous humor, the linker of the combined method is encompassed by the instant claims, is taught to selectively hydrolyze in vitreous humor, and would be expected to provide selective and controlled hydrolysis in vitreous humor ([0031] and [0037] of Ni et al, in particular). It is further noted that, while the instant claims encompass Compound 1 and Compound 2, the instant claims are not limited to Compound 1 or Compound 2. If unexpected results are asserted with a disclosed compound, it is noted objective evidence must be commensurate in scope with the claimed to which the evidence is offered to support. See MPEP 716.02(d).
Claim Rejections - 35 USC § 103
Claims 1-3, 7, 9-11, and 13-18 remain rejected and claims 20-22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Vakalis et al (Scientific Reports, 2015, 5(8627): 1-6).
Ni et al teaches a method of producing synergistic and enhanced efficacy in treating a disease in a subject comprising treating the disease with an antibody-drug synergism (ADS) compound comprising an antibody that blocks a first target in the subject connected via a hydrolysable linker to a small molecule drug that blocks the first target or a second target in the subject ([0004], in particular). Ni et al further teaches said method wherein the disease is an ocular disease ([0005], in particular) and wherein the ADS is delivered to the eye and the linker hydrolyzes in vitreous humor and ocular tissue ([0033], in particular). At [0029] and [0035], Ni et al further teaches said method wherein the disease is age-related macular degeneration (AMD) and wherein the treatment is for choroidal neovascularization (CNV). Ni et al further teaches said method wherein the linker is hydrolyzed with a half-life of 1-24 hours ([0013], in particular). Ni et al further teaches ADS where the antibody is bevacizumab and the small molecule drug is slowly released from the ADS and maintains an effective concentration before the parent ADS is cleared ([0037], in particular), which is a “controlled release fashion.” Ni et al further teaches said method wherein the ADS is PEGylated ([0017], in particular). Ni et al further teaches said method wherein the linker can be esters, amides, carbamates, carbonates, imines, ethers, or phosphates ([0033], in particular).
Ni et al does not specifically teach said method wherein the small molecule drug is dexamethasone. However, these deficiencies are made up in the teachings of Vakalis et al.
Vakalis et al teaches treating subjects with AMD by intravitreal delivering with dexamethasone and bevacizumab to target VEGF results in immediate response of macular edema and improved visual activity (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method to prevent vision impairment in a subject with AMD comprising the method of Ni et al to treat a subject with AMD wherein the Antibody-Drug Synergism (ADS) compound comprises bevacizumab of Ni et al linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al “in a controlled release fashion”) to dexamethasone of Vakalis et al as the small molecule inhibitor because Ni et al teaches ADS synergistically treat ocular diseases, such as AMD, by administering a therapeutic antibody linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al) to a therapeutic small molecule that targets the disease and Vakalis et al teaches treating subjects with AMD by intravitreal delivering with dexamethasone and bevacizumab to target VEGF results in immediate response of macular edema and improved visual activity (Abstract, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. This is also an example of a simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant indicates the skilled artisan would not be motivated with an expectation of success to combined the cited references wherein dexamethasone is linked to bevacizumab with a linker comprising a bond that can be hydrolyzed in the ocular tissue in a controlled release fashion. Applicant further argues the rejection should be withdrawn because Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834) teaches electrostatic conjugation of bevacizumab to nanoparticles was better than chemical conjugation of bevacizumab. Applicant further cites [00030] of the instant specification and indicates the rejection should be withdrawn because claimed compounds can increase the effectiveness of treatment of ocular disease providing advantages including (1) inhibiting more than one key disease mechanism with a single drug molecule and a single injection, (2) increasing effectiveness on retinal fluid removal than either single mechanism alone can achieve, (3) reducing frequency of development of resistance to a monotherapy, (4) novel route for sustained delivery of a small molecule drug to the vitreous, and (5) reducing adverse effects due to frequent intravitreal injections. Applicant further cites compound I and compound II as providing selective and controlled hydrolysis in vitreous humor.
The amendments to the claims and the arguments found in the Reply of 5/20/26 have been carefully considered, but are not deemed persuasive. In regards to the indication the skilled artisan would not be motivated with an expectation of success to combined the cited references wherein dexamethasone is linked to bevacizumab with a linker comprising a bond that can be hydrolyzed in the ocular tissue in a controlled release fashion, the examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method to prevent vision impairment in a subject with AMD comprising the method of Ni et al to treat a subject with AMD wherein the Antibody-Drug Synergism (ADS) compound comprises bevacizumab of Ni et al linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al “in a controlled release fashion”) to dexamethasone of Vakalis et al as the small molecule inhibitor because Ni et al teaches ADS synergistically treat ocular diseases, such as AMD, by administering a therapeutic antibody linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al) to a therapeutic small molecule that targets the disease and Vakalis et al teaches treating subjects with AMD by intravitreal delivering with dexamethasone and bevacizumab to target VEGF results in immediate response of macular edema and improved visual activity (Abstract, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. This is also an example of a simple substitution of one known element for another to obtain predictable results. See MPEP 2143.
In regards to the argument that the rejection should be withdrawn because Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834) teaches electrostatic conjugation of bevacizumab to nanoparticles was better than chemical conjugation of bevacizumab, the examiner disagrees. The rejection is not based on conjugating anything to nanoparticles. Further, this rejection is not based on Liu et al.
In regards to citation of [00030] of the instant specification and indication the rejection should be withdrawn because claimed compounds can increase the effectiveness of treatment of ocular disease providing advantages including (1) inhibiting more than one key disease mechanism with a single drug molecule and a single injection, (2) increasing effectiveness on retinal fluid removal than either single mechanism alone can achieve, (3) reducing frequency of development of resistance to a monotherapy, (4) novel route for sustained delivery of a small molecule drug to the vitreous, and (5) reducing adverse effects due to frequent intravitreal injections, the examiner disagrees. Such advantages are not limited to ADS of Ni et al wherein dexamethasone is the drug of the ADS of Ni et al. Further, such advantages are not limited to ADS of Ni et al wherein the drug of the ADS of Ni et al is a small molecule drug that is an adrenergic receptor alpha agonist or an NSAID. Rather, Antibody-Drug Synergism (ADS) compounds of Ni et al provide all such advantages. See comparison with closes prior at MPEP 716.02(e).
In regards to the citation of compound I and compound II as providing selective and controlled hydrolysis in vitreous humor, the linker of the combined method is encompassed by the instant claims, is taught to selectively hydrolyze in vitreous humor, and would be expected to provide selective and controlled hydrolysis in vitreous humor ([0031] and [0037] of Ni et al, in particular). It is further noted that, while the instant claims encompass Compound 1 and Compound 2, the instant claims are not limited to Compound 1 or Compound 2. If unexpected results are asserted with a disclosed compound, it is noted objective evidence must be commensurate in scope with the claimed to which the evidence is offered to support. See MPEP 716.02(d).
Claim Rejections - 35 USC § 103
Claim(s) 1-3, 7-11, and 13-18 remain rejected and claims 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834) as applied to claims 1-3, 7, 9-11, 13-18, and 20-22 above, and further in view of Bezwada (US 2009/0082540 A1; 3/26/2009).
Teachings of Ni et al and Liu et al are discussed above.
Ni et al and Liu et al do not specifically teach a hydrolysable linker encompassed by instant claim 8. However, these deficiencies are made up in the teachings of Bezwada et al.
Bezwada teaches numerous hydrolysable linkers, including this hydrolysable amide linker of Formula VI on page 14 that encompasses a linker of instant claim 8:
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Bezwada further teaches the hydrolysable linkers can be administered by ocular route ([0286], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Liu et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. This is further an example of a simple substitution of one known hydrolysable liker for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above. Applicant further argues cited references do not teach or suggest linkers of Bezwada et al, such as those of Formula VI on page 14 of Bezwada et al, are hydrolyzed in ocular tissue in a controlled release fashion. Applicant further argues selection of a linker of Bezwada et al would only be possible through the lens of impermissible hindsight and is not a simple substitution of one known hydrolysable liker for another to obtain predictable results.
The amendments to the claims and the arguments found in the Reply of 5/20/26 have been carefully considered, but are not deemed persuasive. In regards to the argument cited references do not teach or suggest linkers of Bezwada et al, such as those of Formula VI on page 14 of Bezwada et al, are hydrolyzed in ocular tissue in a controlled release fashion, the linkers of Bezwada et al are taught to be hydrolysable linkers (see linker of Formula VI on page 14) and to be administered by an ocular route ([0286], in particular). The only reason to administer a construct comprising a hydrolysable linker through an ocular route would be to have the linker hydrolyzed at the site of administration – which would result in a bond of the linker being hydrolyzed in ocular tissue in a controlled release fashion. The examiner asserts it would be obvious to use any hydrolysable linker of Bezwada as the hydrolysable linker of the combined method of Ni et al and Liu et al.
In regards to the argument that selection of a linker of Bezwada et al would only be possible through the lens of impermissible hindsight and is not a simple substitution of one known hydrolysable liker for another to obtain predictable results, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Further, the examiner asserts it would be obvious to use any hydrolysable linker of Bezwada et al in the combined method of Ni et al and Liu et al. Again, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Liu et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. This is further an example of a simple substitution of one known hydrolysable liker for another to obtain predictable results. See MPEP 2143.
Claim Rejections - 35 USC § 103
Claim(s) 1-3, 7-11, and 13-18 remain rejected and claims 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Vakalis et al (Scientific Reports, 2015, 5(8627): 1-6) as applied to claims 1-3, 7, 9-11, 13-18, and 20-22 above, and further in view of Bezwada (US 2009/0082540 A1; 3/26/2009).
Teachings of Ni et al and Vakalis et al are discussed above.
Ni et al and Vakalis et al do not specifically teach a hydrolysable linker encompassed by instant claim 8. However, these deficiencies are made up in the teachings of Bezwada et al.
Bezwada teaches numerous hydrolysable linkers, including this linker of Formula VI on page 14 that encompasses a linker of instant claim 8:
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Bezwada further teaches the hydrolysable linkers can be administered by ocular route ([0286], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Vakalis et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular). This is an example of a simple substitution of one known hydrolysable liker for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Claim Rejections - 35 USC § 103
Claim(s) 1-5, 7, 9-11, and 13-19 remain rejected and claims 6 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834) as applied to claims 1-3, 7, 9-11, 13-18, and 20-22 above, and further in view of Turecek et al (Journal of Pharmaceutical Sciences, 2016, 460-475).
Teachings of Ni et al and Liu et al are discussed above.
Ni et al and Liu et al do not specifically teach that the PEGylated antibody of the ADS of the combined method comprises a linear PEG moiety, a branched PEG moiety, or PEG moiety that is –(CH2-CH2-O-)n where n is 5-30. However, these deficiencies are made up in the teachings of Turecek et al.
Turecek et al teaches a single PEG chain has the structure equivalent to “–(CH2-CH2-O-)n” (Figure 1, in particular), multiple PEGs attached to a molecule are called “PEGmers” (right column on page 461, in particular), and commercial therapeutics include PEGmers where “n” is 6 (left column on page 469, in particular) or 11-17 (Table 1, in particular). Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular) and that attached PEG can be linear, branched, or (left column on page 468, in particular). Turecek et al further teaches prodrugs where a cleavable linker cleaves PEG from the drug upon release of the drug (left column on page 472, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Liu et al wherein the PEGylated antibody of the ADS of the combined method is PEGylated in any manner taught by Turecek et al where cleavage of the hydrolyzable linker separates PEGylated antibody from the dexamethasone because the antibody of the ADS of the combined method is a large molecule and Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above. Applicant further argues a lack of teaching, suggestion, or motivation to select PEG structures of Turecek to achieve a claimed linker that is hydolyzed in ocular tissue in a controlled release fashion. Applicant further argues selection of a Turecek PEG structure as a linker would only be possible through impermissible hindsight.
The amendments to the claims and the arguments found in the Reply of 5/20/26 have been carefully considered, but are not deemed persuasive. In regards to the arguments of a lack of teaching, suggestion, or motivation to select PEG structures of Turecek to achieve a claimed linker that is hydolyzed in ocular tissue in a controlled release fashion and selection of a Turecek PEG structure as a linker would only be possible through impermissible hindsight, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Further, the combined method of method of Ni et al and Liu et al prevents vision impairment in a subject with AMD by administering an Antibody-Drug Synergism (ADS) compound of Ni et al comprising bevacizumab of Ni et al linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al “in a controlled release fashion”) to dexamethasone of Liu et al as the small molecule inhibitor of the ADS. Ni et al teaches such a method wherein the ADS is PEGylated ([0017], in particular). Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular) and Turecek et al further teaches prodrugs where a cleavable linker cleaves PEG from the drug upon release of the drug (left column on page 472, in particular). Therefore, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Liu et al wherein the PEGylated antibody of the ADS of the combined method is PEGylated in any manner taught by Turecek et al where cleavage of the hydrolyzable linker separates PEGylated antibody from the dexamethasone because the antibody of the ADS of the combined method is a large molecule and Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular).
Claim Rejections - 35 USC § 103
Claim(s) 1-5, 7, 9-11, and 13-19 remain rejected and claims 6 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Vakalis et al (Scientific Reports, 2015, 5(8627): 1-6) as applied to claims 1-3, 7, 9-11, 13-18, and 20-22 above, and further in view of Turecek et al (Journal of Pharmaceutical Sciences, 2016, 460-475).
Teachings of Ni et al and Vakalis et al are discussed above.
Ni et al and Vakalis et al do not specifically teach that the PEGylated antibody of the ADS of the combined method comprises a linear PEG moiety, a branched PEG moiety, or PEG moiety that is –(CH2-CH2-O-)n where n is 5-30. However, these deficiencies are made up in the teachings of Turecek et al.
Turecek et al teaches a single PEG chain has the structure equivalent to “–(CH2-CH2-O-)n” (Figure 1, in particular), multiple PEGs attached to a molecule are called “PEGmers” (right column on page 461, in particular), and commercial therapeutics include PEGmers where “n” is 6 (left column on page 469, in particular) or 11-17 (Table 1, in particular). Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular) and that attached PEG can be linear, branched, or (left column on page 468, in particular). Turecek et al further teaches prodrugs where a cleavable linker cleaves PEG from the drug upon release of the drug (left column on page 472, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Vakalis et al wherein the PEGylated antibody of the ADS of the combined method is PEGylated in any manner taught by Turecek et al where cleavage of the hydrolyzable linker separates PEGylated antibody from the dexamethasone because the antibody of the ADS of the combined method is a large molecule and Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above. Applicant further argues a lack of teaching, suggestion, or motivation to select PEG structures of Turecek to achieve a claimed linker that is hydolyzed in ocular tissue in a controlled release fashion.
The amendments to the claims and the arguments found in the Reply of 5/20/26 have been carefully considered, but are not deemed persuasive. In regards to the arguments of a lack of teaching, suggestion, or motivation to select PEG structures of Turecek to achieve a claimed linker that is hydolyzed in ocular tissue in a controlled release fashion, the examiner disagrees. Further, the combined method of method of Ni et al and Vakalis et al prevents vision impairment in a subject with AMD by administering an Antibody-Drug Synergism (ADS) compound of Ni et al comprising bevacizumab of Ni et al linked (via a linker that hydrolyzes in vitreous humor and ocular tissue of Ni et al “in a controlled release fashion”) to dexamethasone of Liu et al as the small molecule inhibitor of the ADS. Ni et al teaches such a method wherein the ADS is PEGylated ([0017], in particular). Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular) and Turecek et al further teaches prodrugs where a cleavable linker cleaves PEG from the drug upon release of the drug (left column on page 472, in particular). Therefore, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al and Liu et al wherein the PEGylated antibody of the ADS of the combined method is PEGylated in any manner taught by Turecek et al where cleavage of the hydrolyzable linker separates PEGylated antibody from the dexamethasone because the antibody of the ADS of the combined method is a large molecule and Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular).
Claim Rejections - 35 USC § 103
Claim(s) 1-5 and 7-19 remain rejected and claims 6 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834) and Turecek et al (Journal of Pharmaceutical Sciences, 2016, 460-475) as applied to claims 1-7, 9-11, and 13-22 above, and further in view of Bezwada (US 2009/0082540 A1; 3/26/2009).
Teachings of Ni et al, Liu et al, and Turecek et al are discussed above.
Ni et al, Liu et al, and Turecek et al do not specifically teach a hydrolysable linker encompassed by instant claim 8. However, these deficiencies are made up in the teachings of Bezwada et al.
Bezwada teaches numerous hydrolysable linkers, including this linker of Formula VI on page 14 that encompasses a linker of instant claim 8:
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Bezwada further teaches the hydrolysable linkers can be administered by ocular route ([0286], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al, Liu et al, and Turecek et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular). This is an example of a simple substitution of one known hydrolysable liker for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Claim Rejections - 35 USC § 103
Claim(s) 1-5 and 7-19 remain rejected and claims 6 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al (US 2019/0030179 A1; 1/31/19) in view of Vakalis et al (Scientific Reports, 2015, 5(8627): 1-6) and Turecek et al (Journal of Pharmaceutical Sciences, 2016, 460-475) as applied to claims 1-7, 9-11, and 13-22 above, and further in view of Bezwada (US 2009/0082540 A1; 3/26/2009).
Teachings of Ni et al, Vakalis et al, and Turecek et al are discussed above.
Ni et al, Vakalis et al, and Turecek et al do not specifically teach a hydrolysable linker encompassed by instant claim 8. However, these deficiencies are made up in the teachings of Bezwada et al.
Bezwada teaches numerous hydrolysable linkers, including this linker of Formula VI on page 14 that encompasses a linker of instant claim 8:
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Bezwada further teaches the hydrolysable linkers can be administered by ocular route ([0286], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Ni et al, Vakalis et al, and Turecek et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular). This is an example of a simple substitution of one known hydrolysable liker for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Double Patenting
Claims 1-3, 7, 9-11, and 13-18 remain rejected and claims 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 6-8 of U.S. Patent No. 12214049 B2 in view of Ni et al (US 2019/0030179 A1; 1/31/19) and Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834). Both patent and the instant claims are drawn to ADS compounds and/or administering ADS compounds to subjects with an ocular disease wherein the ADS compounds comprise bevacizumab antibody attached via a hydrolysable linker to a small molecule anti-angiogenesis inhibitor. The instant claims differ from the patent claims in that the patent claims do not recite the small molecule anti-angiogenesis inhibitor is dexamethasone or that bevacizumab of the ADS is PEGylated. However, these deficiencies are made-up by Ni et al and Liu et al.
Teachings of Ni et al and Liu et al are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method to prevent vision impairment in a subject with AMD comprising the method of Ni et al (encompassed by the patent claims) to treat CMV in a subject with AMD wherein the ADS comprises bevacizumab of Ni et al linked to dexamethasone of Liu et al as the small molecule inhibitor because Ni et al teaches ADS synergistically treat ocular diseases, such as AMD, by administering a therapeutic antibody linked to a therapeutic small molecule the target the disease and Liu et al teaches SNV is the main cause of vision impairment in AMD that can be treated by targeting VEGF with dexamethasone and bevacizumab (Abstract, in particular).
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Double Patenting
Claims 1-3, 7-11, and 13-18 remain rejected and claims 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 6-8 of U.S. Patent No. 12214049 B2 in view of Ni et al (US 2019/0030179 A1; 1/31/19) and Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834), as applied to claims 1-3, 7, 9-11, and 13-18, and in further view of Bezwada (US 2009/0082540 A1; 3/26/2009).
Teachings of Bezwada are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of the patent claims, Ni et al, and Liu et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular). This is an example of a simple substitution of one known hydrolysable liker for another to obtain predictable results. See MPEP 2143.
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Double Patenting
Claims 1-5, 7, 9-11, and 13-19 remain rejected and claims 6 and 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 6-8 of U.S. Patent No. 12214049 B2 in view of Ni et al (US 2019/0030179 A1; 1/31/19) and Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834), as applied to claims 1-3, 7, 9-11, 13-18, and 20-22, and in further view of Turecek et al (Journal of Pharmaceutical Sciences, 2016, 460-475).
Teachings of Turecek et al are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of the patent claims, Ni et al and Liu et al wherein the PEGylated antibody of the ADS of the combined method is PEGylated in any manner taught by Turecek et al where cleavage of the hydrolyzable linker separates PEGylated antibody from the dexamethasone because the antibody of the ADS of the combined method is a large molecule and Turecek et al teaches attaching PEG molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules (Abstract, in particular).
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Double Patenting
Claims 1-5 and 7-19 remain rejected and claims 6 and 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, and 6-8 of U.S. Patent No. 12214049 B2 in view of Ni et al (US 2019/0030179 A1; 1/31/19), Liu et al (International Journal of Nanomedicine, 2019, 14: 8819-8834), and Turecek et al (Journal of Pharmaceutical Sciences, 2016, 460-475) as applied to claims 1-7, 9-11, and 13-22 and in further view of Bezwada (US 2009/0082540 A1; 3/26/2009).
Teachings of Bezwada are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of the patent claims, Ni et al, Liu et al, and Turecek et al wherein the hydrolysable linker is any hydrolysable linker of Bezwada because the combined method administers an ADS comprising a hydrolysable linker that is to be cleaved in vitreous humor and ocular tissue ([0033], in particular) and the hydrolysable linkers of Bezwada are taught be administered by an ocular route ([0286], in particular).
Response to Arguments
In the Reply of 5/20/26, Applicant repeats arguments address above.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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