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 .
Status of the Claims
Claims 1-22 were originally filed June 20, 2022.
The amendment received January 12, 2023 amended claims 5 and 6; cancelled claims 17-22; and added new claims 23-33.
The amendment received April 14, 2026 amended claims 1, 2, 6-10, 13, 27, and 28 and cancelled claims 4, 5, 11, 12, 14-16, 23-26, and 29-33.
Claims 1-3, 6-10, 13, 27, and 28 are currently pending.
Claims 1-3, 6-9, 13, 27, and 28 are currently under consideration.
Election/Restrictions
Applicant's election with traverse of Alzheimer’s disease, XPro1595™ (i.e. present SEQ ID NO: 3 with the following mutations: V1M, R31C, C69V, Y87H, C101A, and A145R; PEGylated at R31C), the function of forming heterotrimers with WT soluble TNF which have reduced or eliminated affinity for binding and signaling of TNFR1 and TNFR2, PEGylation at residue R31C, between 0.1 mg and 2.0 mg per kilogram body weight of the subject per week, and peripheral administration as the species in the reply filed on April 14, 2026 is acknowledged. The traversal is on the grounds that all the neurological disorders are associated with TNF; DN-TNF proteins are well known and characterized and have the same function of effecting the CNS, cross the BBB, etc.; the function is the same for all DN-TNF; the restriction is overly broad and unclear; the ranges overlap; and the claims have a common technical feature of peripheral administration due to the ability to cross the BBB. This is not found persuasive because a search of one neurological disorder may not overlap with a search for another neurological disorder (e.g. a search for stroke may not overlap with a search for Alzheimer’s disease), thus a serious search burden exists. This is not found persuasive because the DN-TNF proteins while requiring some of the same mutations, also encompass alternative and/or additional mutations which cause a structural difference between the DN-TNF proteins and a serious search burden. This is not found persuasive because different mutations may cause differences in function (this is well-known in the art) and will cause a difference in structure leading to a serious search burden. This is not found persuasive because if the attorney of record was unclear regarding the species requirement, the attorney of record should have telephoned the examiner of record for clarification. In addition, specific claims were provided as guidance for potential elections of species. Furthermore, applicants elected PEGylation at residue R31C (i.e. apparently understanding the species requirement). This is not found persuasive because overlapping ranges is not a reason to not request an election of a single, specific species (e.g. a search for one dosage may not overlap with a search for another dosage). This is not found persuasive because a “common technical feature” is not relevant to the present species requirement (i.e. this is not a Lack of Unity requirement for a 371/National Stage application).
In addition, the following is reiterated:
(a) the species require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries);
(b) the species may have a separate status in the art;
(c) the species may raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112;
(d) the species are structurally and/or functionally different.
The requirement is still deemed proper and is therefore made FINAL.
Claim 10 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on April 14, 2026.
Please note: the “capable of” language in withdrawn claim 10 renders the claim indefinite. There are also grammatical issues with the claim.
Priority
The present application is a CON of 14/427,279 filed March 10, 2015 (now U.S. Patent 11,365,229) which claims the benefit of 61/826,922 filed May 23, 2013 and 61/699,230 filed September 10, 2012.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The abstract of the disclosure is objected to because “TNF-” should read “TNF-a”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities: the first line of the specification should be updated to include U.S. Patent 11,365,229.
Appropriate correction is required.
The use of the term XPro1595™ or XPro 1595™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
See paragraphs 9, 16-20, 45, 93, 96, 137, 142, 147-149, 151, 153-161, 167-169, 174, 176, 185, 187, and 194-197. Applicants are also respectfully requested to carefully review the specification for any other occurrences of trade names or trademarks.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 1 is objected to because of the following informalities: a nexus between the preamble and the method step is required (e.g. peripherally administering to the patient in need thereof). Appropriate correction is required.
Claim 1 is objected to because of the following informalities: “selected from” should read “selected from the group consisting of” and the conjunction “and” should be utilized to correlate with the Markush language. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: a conjunction is missing between the last wherein clause and the whereby clause. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: the mutations should be in sequential order. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: “A145R/I97T” should read “I97T and A145R”. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: “A145R/Y87H” should read “Y87H and A145R”. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: “V1M/R31C/C69V/Y87H/C101A/A145R” should read “V1M, R31C, C69V, Y87H, C101A, and A145R”. Appropriate correction is required.
Sequence Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising a sequence of SEQ ID NO: 1” requires only a 2mer of SEQ ID NO: 1, “comprising the sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with any N-/C-terminal additions or any 5’/3’ additions, “consisting of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 and the same length as SEQ ID NO: 1, and “selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3. Any claim requiring a specific percent identity, necessarily requires at least the recited percent identity.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27 and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Paragraph 134 of the originally filed specification provides support for between 0.0001 mg and 2000 mg per kg body weight of the subject per DAY and between 0.1 mg and 2 mg per kg body weight of the subject per DAY (emphasis added). A dosage based on a week is not supported in the originally filed specification.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 6-9, 13, 27, and 28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. One of skill in the art would not be able to determine the scope of the presently claimed method. For example, it is unclear what the scope of “set forth in” is (e.g. open, closed, etc.).
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. One of skill in the art would not be able to determine the scope of the presently claimed method. For example, it is unclear what mutations would result in the desired function.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 contains the trademark/trade name XPro1595™. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated and, accordingly, the identification/description is indefinite.
Claim 27 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 recites the limitation "the subject" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 28 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 28 recites the limitation "the subject" in line 3. There is insufficient antecedent basis for this limitation in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 is dependent in independent claim 1. Independent claim 1 requires administering a DN-TNF variant of SEQ ID NO: 3 with C69V and C101A mutations; one of Q21C, E23C, R31C, or D45C mutations; and one or more mutations which disrupt receptor binding in a receptor interaction domain. Claim 6 simply refers to the function of the DN-TNF variant. Therefore, dependent claim 6 does not alter the reagents utilized in the method or the method steps and fails to further limit independent claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-2, 6-9, 27, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Binette U.S. Patent Application Publication 2012/0189619 published July 26, 2012.
For present claims 1-2, 6-9, 27, and 28, Binette teaches methods of administering XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) to patients with spinal cord injuries daily for a week at 0.25 mg/kg to 20 mg/kg (i.e. 1.75 mg/kg to 140 mg/kg per week) and gene therapy (please refer to the entire specification particularly the abstract; Figures 1-6; paragraphs 7-11, 16, 18-20, 27, 28, 34-46, 48-55, 89, 99-109, 115-122, 127-139; claims).
Therefore, the teachings of Binette anticipate the presently claimed method.
Claims 1-3, 6-9, 13, 27, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lane et al. U.S. Patent Application Publication 2012/0088713 published April 12, 2012.
For present claims 1-3, 6-9, 13, 27, and 28, Lane et al. teach methods of administering XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated); DN-TNF inhibitors comprising V1M, R31C, C69V, Y87H, C101A, and A145R mutations; XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations); XENP345; etc. to patients with Alzheimer’s disease or Parkinson’s disease at 5 mg/ml-500 mg/ml, 0.5 mg/kg-5 mg/kg, daily doses of 0.001 mg/kg/day to 100 mg/kg/day (i.e. 0.007 mg/kg to 700 mg/kg per week) (please refer to the entire specification particularly the abstract; paragraphs 2, 6-8, 14-18, 21-24, 26-28, 30, 32-38, 43-48, 56; Example 1 and 5; claims).
Therefore, the teachings of Lane et al. anticipate the presently claimed method.
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.
Claims 1-3, 6-9, 13, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177 and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
For present claims 1-3, 6-9, 13, 27, and 28, McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
For present claims 1-3, 6-9, 13, 27, and 28, Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
Claims 1-3, 6-9, 13, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Binette U.S. Patent Application Publication 2012/0189619 published July 26, 2012; McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177; and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
For present claims 1-3, 6-9, 13, 27, and 28, Binette teaches methods of administering XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) to patients with spinal cord injuries daily for a week at 0.25 mg/kg to 20 mg/kg (i.e. 1.75 mg/kg to 140 mg/kg per week) and gene therapy (please refer to the entire specification particularly the abstract; Figures 1-6; paragraphs 7-11, 16, 18-20, 27, 28, 34-46, 48-55, 89, 99-109, 115-122, 127-139; claims).
However, Binette does not teach Alzheimer’s disease.
For present claims 1-3, 6-9, 13, 27, and 28, McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
However, Binette does not teach a V1M mutation.
For present claims 1-3, 6-9, 13, 27, and 28, Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™; V1M mutaiton) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor; addition of a V1M mutation) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
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 1-3, 6-9, 13, 27, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 7,244,823 in view of McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177 and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
U.S. Patent No. 7,244,823 claims DN-TNF inhibitors comprising Q21C, R31C, and A145R mutations wherein R31C is PEGylated.
McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
Claims 1-3, 6-9, 13, 27, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 7,687,461 in view of McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177 and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
U.S. Patent No. 7,687,461 claims methods of administering DN-TNF inhibitors comprising R31C, C69V, Y87H, I97T, C101A, and A145R mutations and PEGylation at R31C.
McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
Claims 1-3, 6-9, 13, 27, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 7,446,174 in view of McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177 and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
U.S. Patent No. 7,446,174 claims methods of administering DN-TNF inhibitors comprising V1M, R31C, C69V, Y87H, I97T, C101A, and A145R mutations including XENP268, XENP344, XENP345, XENPO346, XENP550, XENP551, XENP557, XENP1593, XENP1594, and XENP1595 and PEGylation.
McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
Claims 1-3, 6-9, 13, 27, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 7,144,987 in view of McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177 and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
U.S. Patent No. 7,144,987 claims DN-TNF inhibitors comprising a mutation at residue 69.
McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
Claims 1-3, 6-9, 13, 27, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 7,662,367 in view of McAlpine et al., 2009, Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology, Neurobiol Dis, 34(1): 163-177 and Desjarlais et al. U.S. Patent Application Publication 2007/0009477 published January 11, 2007.
U.S. Patent No. 7,662,367 claims DN-TNF inhibitors comprising mutations at residues 21, 31, and 145.
McAlpine et al. teach methods of administering DN-TNF inhibitors to Alzheimer’s patients wherein the DN-TNF inhibitor is XENP345 (i.e. present SEQ ID NO: 3 with I97T and A145R mutations and PEGylated) and administered via intrahippocampal infusion at 0.01 mg/kg/day for 4 weeks (i.e. 0.07 mg/kg/week) and wherein gene therapy was also utilized (please refer to the entire reference particularly the abstract; Introduction; Reagents and Materials; Intrahippocampal infusion of XENP 345 and systemic LPS injections; Stereotaxic surgeries for lentivirus injections; Results; Discussion; Figures 1-8).
Desjarlais et al. teach DN-TNF inhibitors including XENP550 (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations) and XPro1595™ (i.e. present SEQ ID NO: 3 with R31C, C69V, Y87H, C101A, and A145R mutations wherein R31C is PEGylated) and V1M mutations (please refer to the entire specification particularly the abstract; Figures 5, 6, and 8-10; paragraphs 5-8, 17, 18, 20-22, 68; Examples 2, 5, 6; SEQ ID NO: 3).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
All the claimed elements (i.e. method of administering DN-TNF inhibitors to Alzheimer’s patients; XPro1595™) were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions (i.e. XPro1595™ is a DN-TNF inhibitor) and the combination would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because the substitution of one known element (i.e. genus of DN-TNF inhibitor; XENP345) for another (i.e. species of XPro1595™ which is another DN-TNF inhibitor) would have yielded predictable results (i.e. treatment of Alzheimer’s disease) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. utilizing DN-TNF inhibitors to treat Alzheimer’s disease) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Furthermore, applicants’ representative graciously pointed out in the response filed April 14, 2026 that all the neurological disorders are associated with TNF and would benefit from treatment with any DN-TNF variant protein since all the DN-TNF variant proteins cross the BBB, have an effect on the CNS, share similar physical features, structural features, biophysical properties, and act with a common mechanism of action (see pages 6 and 7).
Claims 1-3, 6-9, 13, 27, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,365,229. Although the claims at issue are not identical, they are not patentable distinct from each other because both the present claims and the claims of U.S. Patent No. 11,365,229 are drawn to methods of treating a neurological disorder via administering DN-TNF inhibitors comprising V1M, R31C, C69V, Y87H, I97T, C101A, and A145R mutations including PEGylated XPro1595™ wherein the neurological disorder includes Alzheimer’s disease.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
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McCoy et al., 2008, Intranigral lentiviral delivery of dominant negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats, Mol Ther, 16(9): 1572-1579.
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