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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12 and 19 in the reply filed on 6/28/2023 is acknowledged.
Claims 13-18 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/28/2023.
Claims 1-4, 6-12 and 19 are under consideration in the instant Office Action.
Modified Rejections Necessitated by Amendment
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 1-4, 6-12 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Esue, U.S. Patent 8,318,161 (9/27/2023 PTO-892) and Weisenberg et al., 2005 (IDS, 5/26/2022) in view of Torzewski et a., 2017 (IDS, 4/27/2021) and Yeang et al., 2016 (8/22/2025 PTO-892).
Claim 1 encompasses a method of reducing the severity of, or the likelihood of aortic valve sclerosis or aortic stenosis in a subject, comprising administering an effective amount of an antibody capable of binding to a fragment of ApoB100, and wherein the antibody comprises the HCDRs of SEQ ID NO: 2-4 and the LCDRs of 5-7. The specification further teaches that these CDRs are found in the human monoclonal antibody orticumab (see paragraph 64), which also has the heavy and light chain variable regions of SEQ ID NO: 8 and 9.
Esue teaches a method of treating atherosclerosis in a subject by administering an effective amount of an antibody that binds to oxidized LDL (col 4, lines14-24). As an example of such an antibody to be used, Esue teaches the antibody 2-DO3 (col 8, lines 38-52), comprising the heavy chain variable region of SEQ ID NO: 3, which comprises instant SEQ ID NO:8, and the light chain variable region of SEQ ID NO: 4, which comprises instant SEQ ID NO: 9. See Figure 2 of Esue, which provides these sequences. Thus, as the fully human monoclonal IgG1 2-DO3 antibody comprises the same sequences as instant SEQ ID NO: 8 and 9, and these sequences comprise the HCDRs of SEQ ID NO: 2-4 and LCDRs of 5-7, the 2-DO3 antibody also comprises the CDRs required by instant claims 1, 6-8, 10-11. Esue further teaches that the anti-oxLDL antibody binds "to a protein antigen in LDL (e.g., ApoB-100)" (col 8, lines 29-30) and that the ApoB100 is oxidized (col 16, lines 19-20). Because 2-DO3 comprises the same heavy and light chain variable regions, and thus CDRs, as orticumab, 2-DO3 would inherently possess the ability to bind to a fragment of ApoB100 as recited in instant claims 1, 6-8, 10-11 and 19. Esue teaches that the antibodies are provided in a pharmaceutically acceptable carrier or excipients (col 17, lines 55-66) as in instant claim 9. Esue teaches that the antibody is administered to a human subject by subcutaneous administration (col 18, lines, 45-57) as in instant claim 10.
Claims 8 and 10-11 limits the antibody used in the method of claim 1 to one wherein the antibody comprises orticumab. The instant application does not provide a definition of the term "orticumab", and as such this term has been interpreted broadly as encompassing any antibody comprising the CDRs recited in claim 1.
Esue further teaches that a therapeutically effective amount of the antibody to be used includes "one or more administrations" selected from dosages ranges that include 0.3 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg and 50 mg/kg of patient body weight and may be administered weekly or monthly (col 19, line 4-13) as required in instant claims 10-12. One of ordinary skill in the art would be able to determine the best dose regimen for the patient population to achieve the required treatment through routine optimization )see MPEP § 2144.05). Esue further teaches that dosage may be administered weekly or monthly (col 19, line 11), which meets the limitations of claim 8.
Esue teaches that atherosclerosis plaques are found in the aorta (col 38, lines 15-17). Esue also teaches anti-oxLDL antibodies "prevent the development of atherosclerotic lesions" (col 19, lines 34-35). As such, Esue teaches a method of reducing the likelihood of developing atherosclerosis and thus teaches a method reducing the likelihood of other factors linked to atherosclerosis with an antibody (2-DO3) that meets the limitations of claim 1. Esue does not specifically teach treating aortic valve sclerosis or aortic stenosis as requires in instant claim 1.
Weisenberg teaches that there is an association between aortic valve calcification and atherosclerosis and that atherosclerosis of the aorta is common in patient with aortic stenosis (see abstract and page 29). Weisenberg teaches calcific aortic stenosis is the consequence of active inflammation which is similar to atherosclerosis (see page, 31, 1st column, 2nd paragraph).
Neither reference teaches using Lp(a) as a biomarker to select the patient and determine the effectiveness of the claimed treatment as in instant claims 2-4 and 19.
Torzewski teaches that the lipoprotein(a) is associated with calcific aortic valve stenosis (CAVS; see Highlight). Torzewski teaches that the lipoprotein(a) is a risk factor for CAVS (see page 230, Summary and page 230, bottom of 1st column)). Torzewski teaches that using lipoprotein(a) lowering agents with be the way to reduce CAVS (see page 231, top of 1st column). Torzewski does not specifically teach the treatment methods of the instant claims.
Yeang teaches that Lipoprotein(a),aka Lp(a), comprised of apolipoprotein(a) [apo(a)] and a low-density lipoprotein-like particle, is a genetically determined, causal risk factor for cardiovascular disease and calcific aortic valve stenosis and Lp(a) has a mechanist role in atherosclerosis and aortic stenosis (see abstract). Yeang teaches Lipoprotein(a) is an unique plasma particle composed of a low-density lipoprotein (LDL)-like particle where apolipoprotein B-100 is covalently attached to the hydrophilic, carbohydrate-rich apolipoprotein(a) [apo(a)] (see page 75, 2nd column, 2nd paragraph). Yeang teaches that the pathophysiologic basis of Lp(a) in atherosclerotic and aortic valve disease has been attributed to both its LDL moiety and apo(a) component. Both apoB-100 and apo(a) have been co-localized in human coronary and carotid atheromas, coronary bypass grafts as well as stenotic aortic valves, suggesting a local role of Lp(a) in the development and/or progression of these disease (see page 77, 2nd column, 2nd paragraph). Yeang does not specifically teach the treatment methods of the instant claims.
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 Esue, Weisenberg, Torzewski and Yeang. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Esue teaches the claimed treatment to treat atherosclerosis patient with plaques in the aorta and Weisenberg teaches that atherosclerosis of the aorta is common in patient with aortic stenosis. Therefore, one ordinary skill would be motivated to administer the same treatments used to treat atherosclerosis of the aorta and treat patients with aortic stenosis and expect to have the same effective result. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Torzewski and Yeang teaches that the lipoprotein(a), which is associated with ApoB-100, in involved in both atherosclerosis and aortic stenosis. Yeang teaches that Lp(a) in atherosclerotic and aortic valve disease has been attributed to both its LDL moiety and apo(a) component. Therefore, one would look for patients with raised Lp(a) levels to treat atherosclerotic and aortic valve disease with the method taught by Esue, as in instant claims 2 and 19 and one would want to lower the levels of Lp(a) and to determine the positive effect of the treatment as in the instant claims 3-4 since Lp(a) levels are associated with the etiology of these diseases and would be a good indicator of who suffers from the disease and who is benefiting from the treatments. 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 11/24/2025 have been fully considered but they are not persuasive. Applicant argues that the Esue reference only teaches treating atherosclerosis and that the other references fail to indicate that atherosclerosis and aortic stenosis are medically linked conditions. It was never stated that these two diseases are the same disease or that the stain pathway is also in aortic stenosis. Rather, it has been shown in the art that these diseases occur together often. Therefore, while they may not be the same disease they do have a shared mechanism as disclosed by Yeang, above. Yeang teaches that the pathophysiologic basis of Lp(a) in atherosclerotic and aortic valve disease has been attributed to both its LDL moiety and apo(a) component. Both apoB-100 and apo(a) have been co-localized in human coronary and carotid atheromas, coronary bypass grafts as well as stenotic aortic valves, suggesting a local role of Lp(a) in the development and/or progression of these disease (see page 77, 2nd column, 2nd paragraph). That is the prima facia obvious motivation of the rejection. There is no argument that they are the same disease, atherosclerosis and aortic stenosis, but since they occur in the same patient population, as taught by Weisenberg and Yeang teaches the shared mechanism of both diseases and provides clear teaching that the target for treatment, Lp(a) and its component of ApoB-100 are clearly good targets for treatment. See Holvoet et al., US7,579,159 (9/27/2023 PTO-892), as an example, who teaches using oxLDL antibodies to treat atherosclerosis and artery stenosis. Holvoet teaches that the observed association between the age of the donor and the occurrence of coronary artery disease is in agreement with previous findings that coronary atherosclerosis in the donor heart predisposes to accelerated posttransplant coronary artery stenosis (see column 15, lines 14-18). This supports the idea that when treating an atherosclerosis patient that it would provide a benefit to the patient with aortic stenosis when targeting the Lp(a) pathway. Therefore, using the treatment for atherosclerosis disease taught by Esue would be obvious over Weisenberg, Torzewski and Yeang because it would be targeting the same mechanism of Lp(a) in both atherosclerosis and aortic stenosis or aortic valve sclerosis. Therefore, using the antibody treatment as taught by Esue is supported by the disclosure of Yeang that teaches the mechanism that these antibodies target is the same mechanism that is involved in producing the diseases of both atherosclerosis and aortic stenosis or aortic valve sclerosis. Therefore, one of ordinary skill in the art would have a reasonable expectation of success in using the treatment taught by Esue in atherosclerosis would also be effective in aortic stenosis or aortic valve sclerosis since it targets the same mechanism causes both diseases of Lp(a).
Applicant argues that there are no transgenic mouse or rabbit models and they fail to show a connection between atherosclerosis and aortic stenosis. As acknowledged by the Yeang reference that the disclosed animal models do not reflect all of the aspects of the human diseases, animal models are still viable models that help gleam insight to the potential mechanism of these diseases. Therefore, this argument is not found persuasive because the teaching in the prior art clearly show that one of ordinary skill in the art attribute the same pathway to the different disease and that successful treatments in one may be applied to the other with a reasonable expectation of success. Applicant further argues that while Yeang teaches that Lp(a) will help further the understanding the mechanistic role of Lp(a) in both atherosclerosis and aortic stenosis Yeang fails to establish a proper animal models for these diseases. This is not a requirement to gleam an obvious conclusion. 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, as discussed above, clearly sets forth that while not all pathway points are know, there are sufficient teachings in the prior art to reach reasonable conclusions based on what is already known of the shared mechanism of the two diseases. Finally, it is pointed out that the Lp(a) is not a requirement for treatment as in instant independent claim 1, but as a marker to determine if treatment is providing an intended result based on the dependent claims of 2-4. As already discussed above, the prior art provides clear motivation why one of ordinary skill would be motivated to administer the treatment to the instantly claimed patient population with a reasonable expectation of success. One of ordinary skill would be motivated to use known biomarkers of the shared pathways to determine if treatment was successful since it is already a good indictor in other diseases, working on the same communal pathway.
Therefore, the arguments are not found persuasive.
Conclusion
No claims are allowable.
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.
Advisory Information
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.Any inquiry concerning this communication or earlier communications from the examiner should be directed to AURORA M. FONTAINHAS whose telephone number is 571-272-2952. The examiner can normally be reached on Monday - Friday (8AM - 4PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675