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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/19/2025 has been entered.
Claims 1, 3-4, 11, 46 and new claims 51-56 are pending and under consideration in the instant Office Action.
Withdrawn Rejections
The rejection of claim 1, 3-4, 11 and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-26 of copending Application No. 17/378,618 is withdrawn in view of claim amendments.
The rejection of claim 1, 3-4, 11 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al., US2016/0340420 (1/4/2023 PTO-892) and Heier et al., 2016 (4/13/2022 PTO-892) in view of Lally et al. 2016 (4/13/2022 PTO-892) is withdrawn in view of claim amendments.
New Rejection
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-4, 11, 46 and new claims 51-56 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al., US2016/0340420 (1/4/2023 PTO-892) and Heier et al., 2016 (4/13/2022 PTO-892) in view of Novartis 2017 (instant PTO-892) and Lally et al. 2016 (4/13/2022 PTO-892).
Zhang teaches treating intraocular disorders including diabetic macular edema by administering a high dose of anti-VEGF antibodies suitable for ophthalmic injection. Zhang teaches that the preferred anti-VEGF antibodies include the variable heavy chain SEQ ID NO: 1 and the variable light chain SEQ ID NO: 2 (see paragraphs 22, 27) which are the same sequences found in brolucizumab in instant claim 1. Zhang teaches the that antibodies further encompass an scFV in SEQ ID NO: 3 (see paragraph 24) and the antibody they call antibody 1008 that is disclosed in SEQ ID NO: 4 (see paragraphs 24, 82-83) which are the same sequences as instant SEQ ID NO:3 and SEQ ID NO: 4. The instant specification discloses the instant sequence in SEQ ID NO:3 is known by RTH258 and Brolucizumab and therefore, the SEQ ID NO: 3 in Zhang meets the requirement of Brolucizumab in claim 1. Zhang teaches that these anti-VEGF antibodies treat neovascular ocular diseases including diabetic macular edema (see paragraph 47) and meets the requirement of instant claim 1. Zhang teaches that the subject or patient is referring to humans (see paragraph 49). Zhang teaches that the anti-VEGF antibody has high concentrations including 60mg/ml -120mg/ml for anti-VEGF antibody with the variable heavy chain SEQ ID NO: 1 and the variable light chain SEQ ID NO: 2 (see paragraphs 9-10, 26-27) as in instant claim 11 and new claims 51-52. Zhang teaches that the preferred dose administration into the eye via intravitreal injections includes 3.0 and 6.0 mg in 50 l injection (see paragraphs 4, 18, 52, 85) as in instant claims 1, 46 and new claims 53-54. Zhang does not disclose a dosing regimen of the instant claims.
Heier teaches administering aflibercept, a VEGF antagonist, to treat diabetic macular edema in human patients (see abstract) and using five doses of intravitreal aflibercept injection every 4 weeks for the first five month and then continue administration to every 8 weeks after the first 5 monthly doses (see abstract and page 2377, 2nd column) as in instant claims 1, 3 and 3 and new claims 55-56. Heier teaches assessing the patient for DME disease by using patients with type 1 or 2 diabetes who present with retinal thickening involving the central 1-mm subfield[central subfield] (CST) and best -correlated visual acuity (BCVA) between 73 and 24 letters in the study eye and continue the assessment during treatment and administer additional (rescue) treatments of DME worsened by the criteria of loss of greater than or equal to 10 letter loss after two consecutive visit or greater than or equal to 15 letter los at first visit and when BCVA was no better than baseline (see page 2377, 2nd column) as in instant claims 1, 4 and new claims 55-56. Haier does not specifically teach using the antibody of claim 1 or the 6 or 12-week dose interval.
Novartis 2017 teaches that RTH258 (brolucizumab) administered at 6 mg met the primary and key secondary endpoints in two Phase III studies, HAWK and HARRIER. These pivotal studies enrolled more than 1,800 patients with neovascular age-related macular degeneration (nAMD) and the primary and key secondary efficacy endpoints were non-inferiority of RTH258 to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48, and average mean change over the period of week 36-48, respectively (see page 1). Novartis 2017 teaches that these results clearly and convincingly demonstrate RTH258 has the potential to reduce injection burden while providing excellent visual outcomes (see top of page 2). Novartis teaches that inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases (see page 2). Novartis 2017 teaches that patients in the RTH258 arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits (see page 3) as instant claims 1, 3-4 and new claims 55-56. Novartis clearly shows that the timeline for dosing with RTH258 can be extended based on patient’s response. This clearly shows that RTH258 can have an extended timeline between dosages and still retain their effect in the subject and to reduce injection burden while providing excellent visual outcomes.
Lally teaches different intravitreal anti-vascular endothelial growth factor (VEGF) agents as treatments that are success full in treating diabetic macular edema. Lally teaches that these treatments include aflibercept, ranibizumab, bevacizumab and that new treatments include RTH258 (aka brolucizumab; see abstract and page 765, 2nd column, 2nd paragraph). Lally teaches that the RTH258 (aka brolucizumab) is a humanized, single chain antibody fragment that inhibits VEGF binding of all VEGF-A isoforms, has a small size, 26kDa, when compared to other agents and that the smaller size allows for enhanced penetration of ocular tissues with reduced systemic circulation. Lally teaches that RTH258 was compared to aflibercept in neovascular AMD with injections every 8 weeks for 32 weeks followed by injection every 12 weeks until week 52 as in instant claims 1 and 3 and new claims 55-56. Lally teaches different base interval treatments which include 4, 6 and 8 weeks (for example, see page 760, section 3.1) as in instant claim 1. Lally teaches that eyes were evaluated monthly and could receive rescues treatment. Lally teaches that RTH258 (aka brolucizumab) performed as well as aflibercept and have fewer rescues treatment required when compared to aflibercept. Lally teaches using the RTH258 at 6mg dose (see page 765, 2nd column, 2nd paragraph). The 6 mg dose meets the requirement of the 120mg/ml dose of claim 11 since 6mg in a 50l dose for intravitreal injection would be equivalent to 120mg/ml. While Lally teaches using VEGF antagonists including RTH258 antibody to treat retinal issues, Lally fails to specifically teach the specific dose regiment which includes an assessment at weeks 32, 36, 48, and 72 to determine the intervals are either 6, 8, 12 or 16 weeks.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhang, Heier, Novartis 2017 and Lally. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Zhang and Heier teach that VEGF antagonists are used to successfully treat diabetic macular edema. Zhang teaches using antibodies in SEQ ID Nos: 1-2, 3 and 4, the instantly claimed antibodies, to treat ocular diseases that includes diabetic macular edema while Heier teaches using aflibercept to treat diabetic macular edema. Both Novartis 2017 and Lally teach the RTH258 antibody, a VEGF antagonist and the same antibody of instant claim 1, treats neovascular AMD as well as using aflibercept and that it has a benefit of improved ocular tissue penetration due to its smaller size. Further, the specific dose treatment of the instant claims of an initial treatment of 6 weeks and the intervals of 8, 12 or 16 after the initial 5 doses would be easily obtained thorough routine optimization of the method since the Novartis 2017, Lally and Heier reference already teach dose regiments of 4 weeks for five doses and dose intervals of 8-12 weeks after the initial treatments with routine assessments of the treatments, over 4, 8 and 12 weeks after treatments (32 ,36, 48, 60 and 72 weeks) using the CST and BCVA as the required tests for effectiveness and the continuation of effectiveness over time. One of ordinary skill in the art would be able to determine the best dose regiment through routine optimization (see MPEP § 2144.05) to provide the best regime for treatment of anti-VEGF antagonist since these dose regiments have already been shown to be successful in similar patient populations with the same and different anti-VEGF antagonists. The patient population is similar since both populations, diabetic macular edema and neovascular AMD, both effect the retina adversely due both suffering from abnormal blood vessel growth and are successfully treated with a VEGF antagonist treatment. Further, the prior art Novartis 2017, shows that this specific drug, RTH258, can be successfully administered at 8 and 12 week intervals, which speaks to the fact that the time frame for administration for this specific drug may be extended and still retain its effectiveness. The prior art’s teaching show that RTH258 is effective in AMD and DME (edema reduction) and that it can be administered at a reduced frequency as other similar drugs and still retain and maintain its effectiveness over time and reduces the injection burden and all its associated adversities. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Response to Arguments
Applicant's arguments filed 9/19/2025 have been fully considered but they are not persuasive. Applicant argues that the combination of references fails to teach all of the claimed limitations or provide the motivation to administer the drug to DME subject on the instantly claimed dosage regime, specifically that none of the references explicitly teach brolucizumab at five loading doses at 6 weeks intervals to treat DME. This is not found persuasive because the Lally and Heier references already teach dose regiments of 4 weeks for five doses and dose intervals of 8 weeks after the initial treatments with routine assessments of the treatments using the CST and BCVA as the required tests for effectiveness. These references clearly teach that multiple loading doses are favored and the dose intervals may be adjusted based on routine optimization. The new Novartis 2017 reference already shows that 8 and 12 week intervals are already successful in similar treatments for AMD with RTH258. It is pointed out that this rejection is not anticipatory but rather an obvious rejections that looks at the prior art to guide one of ordinary skill in determining viable treatments and use similar treatments, such as aflibercept which is a similar drug to brolucizumab (RTH258), to provide guidance on their treatment regimen. Further, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). The prior art, in regards to RTH258, clearly shows that the timeline may be expanded with a reasonable expectation of success since increasing time intervals does not affect the progression of the retinal diseases in diseases such as DME and would reduce the potential for injection injury associated with these types of administration to the eye.
Applicant continue to argue that only brolucizumab, out of 7 VEGF antagonists, demonstrates that the ability to sustain a DME patient on the claimed dosing regimen by four week to q12w/q16w as claimed. This is not found persuasive and it is also pointed out the g16w is not always required and one of the embodiments only requires 12 week intervals which already taught by Lally and the new Novartis 2017 reference. Applicant argues that this is a unique outcome and not an expected outcome, as argued by the office. In response to applicant's argument 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). The Lally reference explicitly calls out the specific brolucizumab, RTH258, was capable of sustaining a DME patient on the claimed dosing regimen by four week to q8w/q12w. Lally also teaches that the ranibizumab group also received injects every 8 and 12 weeks (see page 765, 2nd column, 2nd paragraph) therefore, speaks to the idea of an extended dose timeline, such as the 6 week intervals in the loading dosages and the 8 ,12 and even 16 week interval for continuing treatments would be sustainable and reasonable to try. Since this was already taught in the prior art, it would be an expected result and therefore, not surprising or unexpected since it had already been establish as an effect of the claimed treatment to sustain a DME patient on the claimed dosing regimen by four week to q12w by using brolucizumab. It is also pointed out that applicant only argues to the q16w dose regimen and it is noted that this is only one of the possible dose regimens and is a conditional dose regimen as long as conditions are met since claim 1 states:
“…d) at week 72 the patient's q12w regimen is extended by 4 weeks, to a q16w
regimen, or the patient's q8w regimen is extended by 4 weeks, to a q12w
regimen, if the patient's disease activity is not worsening for multiple consecutive
assessments, wherein the disease activity is assessed for relevant improvements of best corrected visual acuity (BCV A}, reduction of central subfield thickness (CST), reduction of fluid accumulation, or decreased severity of diabetic retinopathy.”
Finally, dependent claims 3 and 26 only call for fq8w or q12w and do not require the q16w as argued by applicant. Therefore, the claim embodiments are not limited to the q16w embodiment that is being argued by the applicant.
The applicant argues that they have unexpected results and that the KERSTREL and KITE disclose that 6mg of brolucizumab show robust visual gains in the claimed dose regiment. The brolucizumab (RTH258) treatment was compared to aflibercept treatment. This is not found persuasive and there is no unexpected result since the prior art already taught that the claimed VEGF antagonist of brolucizumab (aka SEQ ID NO:4) would treat DME and that similar VEGF antagonists, like aflibercept, were successful in treating DME when placed in similar dose regiments with the same dosage requirements. Lally teaches that RTH258 (aka brolucizumab) performed as well as aflibercept and have fewer rescues treatment required when compared to aflibercept. Lally teaches using the RTH258 at 6mg dose (see page 765, 2nd column, 2nd paragraph). Therefore, the positive response for brolucizumab in DME patients is not found surprising or unexpected and the arguments are not found persuasive. The Lally reference clearly teaches that the brolucizumab treatment required fewer rescues which speaks to the fact that dosage administration can be administered over longer periods of time and still keep a positive effect in the subjects. There is no unexpected result since the prior art already taught the required treatment with similar dosages and dose regimens to produce an effective treatment. Please see MPEP 7106.0 (a), I, which states that “a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).“ The evidence provided by applicant of unexpected results falls into the additive sweetness combination example and does not show a greater than expected outcome and therefore, the instant invention is obvious over the combination of references. The results provided by applicant did not show greater than average result since the prior art already taught the same patient population and the drug dosage, the only thing that was different was the timing of the drug intervals and the prior art all provided clear guide points in the art to extend those times with a reasonable expectation of success in maintaining and retaining the gained visual improvement. The prior art clearly set forth the reasonable expectation of extending the drug intervals for RTH258 and not lose ground on visual gain improvement.
MPEP 716.02 (b) teaches that the burden is on applicant to establish their results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."). Applicant is merely concluding that their results are superior without showing statistical and practical significance.
The evidence of unexpected results must be commensurate in scope with the claimed invention (see MPEP §716.02(d)). Evidence pertaining to secondary considerations must be taken into account whenever present; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (fed. Cir. 2007) (see MPEP §2145). Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
Further regarding the claim of unexpected results, case law holds that although the record may establish evidence of secondary consideration which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. V. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989).
That applicant found the treatment with brolucizumab (RTH258) to be an effective therapy for subjects with DME with an extended interval time in the loading dose from 4 weeks as taught in the prior art to 6 weeks and continual treatments at 8, 12 and 16 week intervals does not establish nonobviousness. “Scientific confirmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention.” PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363—64 (Fed. Cir. 2007).
Therefore, the applicant’s argument are not found persuasive and the newly amended 103 rejection which now incorporated Novartis 2017 sets forth the reasons why the instant claims are obvious over the prior art.
Conclusion
No claims are allowed.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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