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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Election/Restrictions
Applicants elected calreticulin with at least 85% identity to SEQ ID 1 for topical treatment of age related macular degeneration at a concentration of 25-250 ng/mL with traverse in the reply filed on 28 May, 2025. The traversal was found unpersuasive, and the election/restriction requirement made final in the office action of 18 June, 2025.
Claims Status
Claims 1-6 and 8-26 are pending.
Claims 1, 20, and 22 have been amended.
Claims 9-13, 16-19, 23, and 25 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claims 1-6, 8, 9, 12-15, 20, 21, and 24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite due to uncertainty as to the scope of the claim limitation “calreticulin” is hereby withdrawn due to amendment.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 20-22, 24, and 26 are rejected under 35 U.S.C. 101 because they read on a natural phenomenon.
The Supreme Court has given a 3 part test for eligibility under this statute:
1) Is the invention drawn to a process, machine, manufacture, or composition of matter?
2a) If the invention passes the first test, does a judicial exception apply?
2b) If a judicial exception applies, is there anything beyond the judicial exception?
Applying the test:
1) The claims are drawn to calreticulin formulations, a composition of matter, passing the first test.
2a) Varricchio et al (Front. Cell Develop. Biol. (2017) 5 article 96) states that calreticulin is a calcium binding protein expressed by all cells (1st page, 1st paragraph). This means it is a naturally occurring material. Tosato et al (US 20050205018, cited by applicants) states that the sequence of SEQ ID 1 is the naturally occurring sequence (paragraphs 47 and 11). The claims also require one or more buffering agents, but that can also be met by naturally occurring compounds, such as acetate, citrate, or phosphate. A claim specifies the container (dropper bottle), but just placing a formulation in a container is not enough to render the claims patent eligible.
2b) At least some claims can be met with just a mixture of calreticulin and a buffer solution. There is no evidence of record that a buffer will cause any significant difference in properties of the same compound at the same pH and ionic strength. Nor does the container impart special properties to the formulation. Thus, the claims are not patent eligible.
response to applicant’s arguments
Applicants argue that, as a pharmaceutical formulation in a buffer, the claimed formulations are significantly different than the naturally occurring material.
Applicant's arguments filed 18 Sept, 2025 have been fully considered but they are not persuasive.
Applicants have spent a great deal of ink describing the differences between the claimed formulations and naturally occurring calreticulin in vivo. However, none of these differences affect the properties of the polypeptide in any significant way. In essence, applicants are arguing that they have modified the matrix in which the material is naturally found; that the hand of man is required to make the formulation. However, the hand of man test has been superseded by the three part test described in the rejection.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 5, 6, and 8 are rejected under 35 U.S.C. 102((a)(1)) as anticipated by Tosato et al (US 20050205018, cited by applicants). Please note that this rejection does not read on applicant’s elected species.
Tosato et al discuss calreticulin to inhibit angiogenesis (title). Note that this includes the full length human calreticulin (paragraph 84), which includes SEQ ID 1 of the examined claims. This can be used for treating diseases where angiogenesis is a factor, including ocular neovascular diseases, such as macular degeneration, diabetic retinopathy, and retrolental fibroplasia (paragraph 20). Recombinant proteins from E. coli were produced (paragraph 118) and purified into Tris buffer (paragraph 120). Subjects can be human (paragraph 100).
Tosato et al discuss using calreticulin to treat macular degeneration, anticipating claims 1-3.
This is the same treatment to the same patient population, so it will inherently have the same effects. Thus, the reference anticipates claim 5.
Tosato et al use a sequence including SEQ ID 1 of the examined claims, and mentions human patients. Thus, the combination of references renders obvious claims 6 and 8.
response to applicant’s arguments
Applicants argue that the disclosure is speculative, that there is no experimental data with respect to these disorders, so the reference is not enabled, that Friis et al was not able to demonstrate what applicants have claimed, that calreticulin was found to promote the progression of tumors, that there is a bias against longer polypeptides, and that it is unexpected that the claimed methods are effective.
Applicant's arguments filed 18 Sept, 2025 have been fully considered but they are not persuasive.
Applicants argue that the disclosure is speculative, there is no experimental data with respect to these disorders, and so the reference is not enabled. This argument is supported by a citation to Friis et al and vague statements that calreticulin promotes tumor growth. A reference is presumed to be enabled (MPEP 2121(I)), and there are multiple references on record (such as Bee et al, cited in applicant’s arguments) that show that fragments of calreticulin is antiangiogenic, supporting this presumption. Applicants point to Friis et al to say that a person of skill in the art would presume it to be ineffective. Friis et al state that a specific assay does not show angiogenesis inhibition, so the mechanism of action must be different than the assay assumes (p771, 8th paragraph). In other words, the reference states that the material is antiangiogenic, but that the mechanism is not known. Applicants argue that calreticulin promotes tumor growth. However, it is not clear how this shows that the material does not inhibit angiogenesis. Nor are the references describing this cited; this is merely attorney arguments (MPEP 716.01(c)(II)). In other words, applicants have not provided sufficient evidence to overcome the presumption of enablement.
Applicants argue that there is a bias against longer polypeptides. Applicants have not described how this overcomes the rejection.
Applicants argue that it is unexpected that the invention works as claimed. It is not clear how an invention working exactly how the prior art suggests it will is unexpected, or how it overcomes the 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 8, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Tosato et al (US 20050205018, cited by applicants) in view of Cousins (Mod. Retina. Ophthalmol. (2016)) and Stamboulis et al (US 20160339079).
Tosato et al discuss calreticulin to inhibit angiogenesis (title). Note that this includes the full length human calreticulin (paragraph 84), which includes SEQ ID 1 of the examined claims. This can be used for treating diseases where angiogenesis is a factor, including ocular neovascular diseases, such as macular degeneration, diabetic retinopathy, and retrolental fibroplasia (paragraph 20). Recombinant proteins from E. coli were produced (paragraph 118) and purified into Tris buffer (paragraph 120). Subjects can be human (paragraph 100). The invention will stop angiogenesis caused by a number of growth factors, including VEGF (paragraph 195). It can be administered by any means that achieve the intended purpose (paragraph 189). Dosage will vary based on the nature and severity of the condition to be treated, with the final determination made by an attending clinician (paragraph 190).
As noted above, this reference anticipates claims 1-3, 5, 6, and 8.
The difference between this reference and the remaining claims is that this reference does not discuss topical administration for age related macular degeneration, and does not discuss the claimed concentrations.
Cousins discusses a topical treatment for neovascular age related macular degeneration (title). This is a VEGF inhibitor (1st page, 1st paragraph), which eliminates the risks associated with intravitreal injections of anti VEGF antibodies (1st page, 2nd paragraph). A phage I/II dose ranging trial was used to establish dosage, safety, and tolerability (2nd page, 2nd paragraph). This reference relates age related macular degeneration to angiogenesis, and discusses topical administration.
Stromboulis et al discuss transmembrane delivery systems (abstract). This comprises a polypeptide of up to 20 AA in length comprising a number of basic amino acids (paragraph 12) which may be covalently or non-covalently bound to the pharmaceutical agent (paragraph 32). They can be formulated as eye drops in saline for applying to the surface of the eye (paragraph 36). Among the disorders the delivery system can treat is macular degeneration (paragraph 43), indicating that it will carry a drug to the proper portions of the eye.
Therefore, it would be obvious to use the material of Tosato et al in the disorder of Cousins, as the disorder is described as having properties that Tosato et al has stated will render their formulations useful (angiogenesis caused by VEGF). As this is a subgenus of a genus of disorders that Tosato et al has stated can be treated (macular degeneration), an artisan in this field would attempt this therapy with a reasonable expectation of success.
Furthermore, it would be obvious to use the method of Stromboulis et al, to deliver the drugs topically and avoid the hazards of injection noted by Church. As Stromboulis et al discuss treatment of macular degeneration, an artisan in this field would attempt this formulation with a reasonable expectation of success.
Alternatively, applicants have placed on record a statement that the various methods are obvious over each other in their response to election/restriction requirement posted 28 May, 2025.
Tosato et al teaches SEQ ID 1 to treat macular degeneration. Cousins renders obvious using the material for age related macular degeneration, rendering obvious claim 4.
Cousins and Stromboulis et al together render obvious topical administration, which will require some sort of dropper administration. While the references do not specify the same concentration claimed by applicants, this is considered optimization rather than inventive. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”) (MPEP2144.05.II). This is supported by statements by Tosato et al about adjusting the dosage, and a clinical trial to determine dosing by Cousins et al. Thus, the combination of references renders obvious claims 14 and 15.
response to applicant’s arguments
Applicants argue that the primary reference is not enabled, that there is no reasonable expectation of success, that there is no reason to combine, and that the rejection missed a limitation.
Applicant's arguments filed 18 Sept, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the enablement of the primary reference are similar to those given with respect to the rejection under 35 USC 102, above, and were answered there.
Applicants argue that there is no reason to combine. However, applicants have not stated why the reasons given in the rejection (to treat the disorder of Cousins et al and to avoid the problems with the method of Church) are improper or incorrect. Without such reasons, this argument is merely a statement that applicants disagree with the rejection.
Finally, applicants argue that the rejection missed a limitation. However, the limitation that was missed is never disclosed by applicants.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8, 14, and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 7 of U.S. Patent No. 9,796,971 in view of Tosato et al (US 20050205018, cited by applicants), Cousins (Mod. Retina. Ophthalmol. (2016) and Stamboulis et al (US 20160339079).
Competing claim 1 describes a method of generating an endoplasmic reticulum chaperone protein, comprising all the steps of examined claim 25, save formulating in a solution suitable for ocular administration. Competing claim 4 specifies a Markush group of proteins, including calreticulin, and competing claim 7 specifies that specific protein.
The difference between the competing claims and the examined claims is that the competing claims do not specify methods of use, and do not describe the reconstitution step of examined claim 25.
Tosato et al discuss calreticulin to inhibit angiogenesis (title). Note that this includes the full length human calreticulin (paragraph 84), which includes SEQ ID 1 of the examined claims. This can be used for treating diseases where angiogenesis is a factor, including ocular neovascular diseases, such as macular degeneration, diabetic retinopathy, and retrolental fibroplasia (paragraph 20). Recombinant proteins from E. coli were produced (paragraph 118) and purified into Tris buffer (paragraph 120). Subjects can be human (paragraph 100). The invention will stop angiogenesis caused by a number of growth factors, including VEGF (paragraph 195). It can be administered by any means that achieve the intended purpose (paragraph 189). Dosage will vary based on the nature and severity of the condition to be treated, with the final determination made by an attending clinician (paragraph 190). This reference discusses the utility of the sequences of the competing claims.
Cousins discusses a topical treatment for neovascular age related macular degeneration (title). This is a VEGF inhibitor (1st page, 1st paragraph), which eliminates the risks associated with intravitreal injections of anti VEGF antibodies (1st page, 2nd paragraph). A phage I/II dose ranging trial was used to establish dosage, safety, and tolerability (2nd page, 2nd paragraph). This reference relates age related macular degeneration to angiogenesis, and discusses topical administration.
Stromboulis et al discuss transmembrane delivery systems (abstract). This comprises a polypeptide of up to 20 AA in length comprising a number of basic amino acids (paragraph 12) which may be covalently or non-covalently bound to the pharmaceutical agent (paragraph 32). They can be formulated as eye drops in saline for applying to the surface of the eye (paragraph 36). Among the disorders the delivery system can treat is macular degeneration (paragraph 43), indicating that it will carry a drug to the proper portions of the eye.
Therefore, it would be obvious to use the material of the competing claims in the disorder of Cousins, as the disorder is described as having properties that Tosato et al has stated will render such formulations useful (angiogenesis caused by VEGF). As this is a subgenus of a genus of disorders that Tosato et al has stated can be treated (macular degeneration), an artisan in this field would attempt this therapy with a reasonable expectation of success.
Furthermore, it would be obvious to use the method of Stromboulis et al, to deliver the drugs topically and avoid the hazards of injection noted by Church. As Stromboulis et al discuss treatment of macular degeneration, an artisan in this field would attempt this formulation with a reasonable expectation of success.
Alternatively, applicants have placed on record a statement that the various methods are obvious over each other in their response to election/restriction requirement posted 28 May, 2025.
response to applicant’s arguments
Applicants reference their arguments with respect to the rejection under 35 USC 103, above, which are discussed there.
New Rejections
Claim Rejections - 35 USC § 103
The legal basis for rejections under this statute was given above, and will not be repeated here.
Claim(s) 1-6, 8, 14, 15, 20-22, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Tosato et al (US 20050205018, cited by applicants) in view of Cousins (Mod. Retina. Ophthalmol. (2016)), Stamboulis et al (US 20160339079), and Izutsu (in Therapeutic proteins (2005) ISBN 1-58829-390-4, p287-292).
Tosato et al discuss calreticulin to inhibit angiogenesis (title). Note that this includes the full length human calreticulin (paragraph 84), which includes SEQ ID 1 of the examined claims. This can be used for treating diseases where angiogenesis is a factor, including ocular neovascular diseases, such as macular degeneration, diabetic retinopathy, and retrolental fibroplasia (paragraph 20). Recombinant proteins from E. coli were produced (paragraph 118) and purified into Tris buffer (paragraph 120). Subjects can be human (paragraph 100). The invention will stop angiogenesis caused by a number of growth factors, including VEGF (paragraph 195). It can be administered by any means that achieve the intended purpose (paragraph 189). Dosage will vary based on the nature and severity of the condition to be treated, with the final determination made by an attending clinician (paragraph 190).
Cousins discusses a topical treatment for neovascular age related macular degeneration (title). This is a VEGF inhibitor (1st page, 1st paragraph), which eliminates the risks associated with intravitreal injections of anti VEGF antibodies (1st page, 2nd paragraph). A phage I/II dose ranging trial was used to establish dosage, safety, and tolerability (2nd page, 2nd paragraph). This reference relates age related macular degeneration to angiogenesis, and discusses topical administration.
Stromboulis et al discuss transmembrane delivery systems (abstract). This comprises a polypeptide of up to 20 AA in length comprising a number of basic amino acids (paragraph 12) which may be covalently or non-covalently bound to the pharmaceutical agent (paragraph 32). They can be formulated as eye drops in saline for applying to the surface of the eye (paragraph 36). Among the disorders the delivery system can treat is macular degeneration (paragraph 43), indicating that it will carry a drug to the proper portions of the eye.
As noted above, these references render obvious claims 1-6, 8, 14, and 15.
The difference between these references and the remaining claims is that these references do not discuss a formulation with phosphate buffer.
Izutsu discusses stabilization of polypeptide formulations (title). The process of developing a stable formulation starts with optimizing the pH and ionic strength, then determining what excipients affect stability (p289, section 3.1 “preformulation studies”). Among the buffers suggested include phosphate compounds (table 2, p288, bottom of page).
Therefore, it would be obvious to use phosphate buffers in an attempt to optimize the stability of the formulation, as Izutsu suggests these buffers for this purpose. As this is a general method to optimize polypeptide formulations, an artisan in this field would attempt this method with a reasonable expectation of success.
Izutsu suggests phosphate buffers, rendering obvious claim 20.
There is nothing in the formulation preventing direct administration, rendering obvious claim 21.
Differences in concentration are not considered a patentable distinction, absent secondary considerations (MPEP 2144.05(II)), rendering obvious claims 22 and 26.
Stromboulis et al discuss eye drops, rendering obvious claim 24.
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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
Examiner interviews are available via telephone 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, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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