Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Applicant’s amendment and response filed 10/6/25 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election of Group I in Applicant’s amendment and response filed 3/18/25.
Claims 1, 4, 5, 9-11, 16, 17 and newly added claims 21-23 are presently being examined.
3. Applicant’s amendment filed 10/6/25 has overcome the prior rejection of record of claims 1, 3-8, 11, 16-18 and 20 under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Applicant has added a step of making the G4, monitoring the level of G4 in the recipient, and administering additional G4 to the tissue transplant recipient.
4. Applicant’s amendment filed 10/6/25 has overcome the prior rejection of record of claims 1, 2, 4-11 and 16-20 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 (written description rejection.)
Applicant has amended the claims to recite a step of making the G4.
5. 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.
6. Claims 1, 4, 5, 9-11, 16, 17 and 21-23 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
This is a new ground of rejection necessitated by Applicant’s amendment filed 10/6/25.
The specification does not disclose how to use the instant invention:
a) (for claims 1, 4, 5, 9-11, 16 and 17) a method comprising:
determining a donor-specific human leukocyte antigen of a tissue transplant recipient,
determining a ratio of the tissue transplant recipient for a level of an IgG subclass 4 antibody (G4) for the antigen with respect to a level of another IgG subclass antibody for the antigen;
making the G4;
based on the ratio, administering an amount of the G4 (specific for the antigen) to the tissue transplant recipient “;
monitoring the level of the G4 in the recipient;
based on the monitoring, adjusting at least a G4 does amount or a G4 dose frequency; and
based on the adjusting, administering additional G4 to the tissue transplant recipient as is recited in instant base claim 1, and including the limitations recited in the dependent claims (and note that instant dependent claim 11 recites “comparing a monitored level of the G4 of the tissue transplant recipient to a target level of the G4 for the tissue transplant recipient); or
b) (for claims 21-23) a method comprising making a bank of proteins; determining a donor-specific HLA antigen of a tissue transplant recipient; determining a ratio of the tissue transplant recipient for a level of an IgG4 antibody for the antigen with respect to a level of another IgG subclass antibody for the antigen; selecting the G4 from the bank of proteins, wherein the bank of proteins comprises different G4s (specific for an HLA antigen); based on the ratio, administering an amount of the selected G4 to the tissue transplant recipient; monitoring the level of the G4 in the recipient; based on the monitoring, adjusting at least a G4 dose amount or a G4 dose frequency; and based on the adjusting, administering additional selected G4 to the tissue transplant recipient as is recited in instant base claim 21, and including the limitations recited in the dependent claims.
The specification has not enabled the breadth of the claimed invention because the claims encompass a method comprising determining a ratio in a tissue transplant recipient for a level of an IgG4 subclass antibody (G4) for a donor specific HLA antigen with respect to a level of another IgG subclass antibody for the said donor specific HLA antigen, making the G4, based on the said ratio, administering an amount of the G4 to the said recipient, monitoring the level of the G4 in the said recipient, based on the monitoring, adjusting at least a G4 dose amount or a G4 dose frequency, and based on the adjusting, administering additional G4 to the tissue transplant recipient, however there is no nexus as to the critical target ratio G4/other IgG subclasses and/or level of G4; nor is there any disclosure for a target level of the G4 for the tissue transplant recipient. It is unpredictable what that ratio actually is for administration and it is unpredictable what the monitored level of G4 in the recipient is for administering additional G4 to the recipient, given the lack of guidance in the specification, the breadth of the types of tissue transplants, the variability of ratios of G4/other IgG subclasses in patients with transplant outcome, and the state of the art.
The specification discloses at [0051] that “ratios of IgG subclasses may be beneficial as to making an assessment, planning treatment, etc.” The specification further discloses HLA DSA (donor specific antibodies specific for HLA) is a risk factor for graft survival and has been linked with rejection and poor prognosis; however “DSA is not significantly associated with graft failure wherein DSA was 1000 MFI, and some have considered preformed and/or de novo DSA low risk factors for transplants…Therefore the conjecture of HLA DSA hazards is an open question” ([0062]).
The specification discloses that data indicate that the IgG subclasses vary greatly in their ability to cause inflammation and tissue destruction, with IgG1 and IgG3 activating complement and functioning through phagocyte high affinity Fc receptors, IgG2 being a poor complement activator and having low binding to high affinity Fc receptors, and IgG4 (G4) having no complement fixing activity and binding to an inhibitory Fc receptor. The specification discloses that in transplant patients with G1 and G3, DSAs are likely to have a high probability of graft destruction through complement activation and phagocytosis; whereas, for example, G2 and/or G4 may have a beneficial effect ([0063]).
The specification discloses seven case studies performed for subjects that included three renal and four heart transplant patients wherein analyses provide data for anti-HLA DSA G1-G4 subclasses ([0064]). The specification discloses that as an example, complement fixing C1q binding and G3 DSA have been shown to be a risk factor for renal and liver transplant recipients, G1 and G3 were found to be associated with rejection and more class II was directed against HL-DQ after one year post transplant ([0080]). The specification discloses a recipient with stable function and a G4 DSA (patient FL) who was monitored for over two years with the most recent subclass analysis showing only G4 ([0081]). The specification further discloses that G4 also inhibits immune complex formation and can inhibit crosslinking and complement [fixation] of G1 and G3 Ig subclasses ([0081]). Inspection of Table 4 of the instant application reveals that patient “FL” had a heart transplant and at 36 months through 39 months had both G1 and G4 DSA antibodies at different ratios, G2 and G4 at one ratio, and G4 alone at 52 months, and with some timepoints indicating DSA against different HLA class II molecules within the one patient. Note the lack of data for the ratio of G4/G3 in this patient. These said G4/G1or G4/G2 ratios for this one patient were 2.2, 2.6, 3.6, 4.8, respectively.
The specification at [0071] and Table1 shows DSA for a renal transplant recipient “MD”. This patient had seven DSAs, with G1 DSAs to two different HLA molecules and no other G1-G4 DSAs found. By POD (post operative day) 9, the DSAs were predominately G1 and G3 with no G4. On POD 30 there were still strong complement fixing DSAs and the patient had lost renal function and was nephrectomized on POD 33. Five months later G1 and G3 persisted in all the SA DSAs, but there was a G4 subclass against HLA-A33 and HLA-DR7. Those latter G4/G3 ratios were 0.45 and 0.18, respectively.
The specification at [0072] and Table 1 shows a renal transplant recipient “MY” who had G3 subclass DSAs against one HLA-DR4 antigen, after rejection at 3 weeks and measurement at 1 month, the patient had both G3 and G1 DSAs against the same HLA antigen, G1 DSAs against two different class II HLA antigens, and no G4 DSAs. The specification at [0073] and Table 1 indicates that this patient had G3 subclass DSAs pre-transplant, and G1 or G3 DSAs after rejection at 5 months. The specification at Table 2 shows three heart transplant patients having G1, G2 and, or G3 subclass DSAs after transplantation.
However, none of these examples at [0071]-[0073] disclose any information on G4/G1, G4/G2 and/or G4/G3 ratios for administration or for adjusting and administering further G4 doses. Nor were any of the patients in the examples treated by administration of G4 anti-DSAs. In fact Table 3 of the instant specification indicates a collection of these patients having no G4 having good function, poor function, or graft loss, while, as enunciated above, the monitored levels of the patient in Table 4 indicated both G4/G1 and G4/G2 anti-HLA DSAs with stable function over 60 months.
The specification does not disclose any working examples of administering G4 based upon any G4/other IgG subclass ratios or levels of G4 for administering additional G4 anti-HLA DSAs.
It is unpredictable, given lack of correlation and guidance, that ratios of G4/other IgG subclasses of anti-HLA DSAs observed in the sera of one to seven patients having one of two types of tissue transplant can be used for deciding ratio for administration to these said patients or to all patients having anti-HLA DSAs in the context of all tissue transplants.
Evidentiary reference Cicciarelli et al (Human Immunology, SUPPL. 1, pp. 30. Abstract Number: OR35. Meeting Info: 41st Annual Meeting of the American Society of Histocompatibility and Immunogenetics. Savannah, GA, United States. 28 Sep 2015-02 Oct 2015 ISSN: 0198-8859, STN accession number 0052181295, of record) teaches that the association between donor specific antibodies (DSA) and renal transplant rejection has been generally established, there are cases when a DSA is present without rejection. Cicciarelli et al further teach that IgG4 was seen in 10 of the 23 renal transplant recipients’ sera, but always along with complement fixing IgG1. “The detection of IgG4 subclass did not correspond to any enhanced graft survival outcome…We could not demonstrate any enhanced benefit of IgG4. However, in this cohort of patients, IgG4 appeared coincidently to IgG1, and we have previously seen excellent function in patients when IgG4 DSA exists alone”. See entire abstract.
There is insufficient guidance in the specification as to how to use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
7. Applicant’s amendment filed 10/6/25 has overcome the prior rejection of record of claims 16-20 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.
8. 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.
9. Claims 5 and 21-23 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.
This is a new ground of rejection necessitated by Applicant’s amendment filed 10/6/25.
a) Claim 5 is indefinite in the recitation of “wherein one or more non-binding portions of the G4 block an immune response cascade” because it is not clear what is meant. Applicant should amend the claim to recite ‘one or more non-antigen-binding portions of the G4’ if that is what is meant.
b) Claim 21 is indefinite in the recitation of “wherein the bank of proteins comprises different G4s” because it is not clear what is meant, i.e., if the different G4s are IgG4 subclass antibodies specific for the same donor-specific HLA molecule or if the different G4s are IgG4 subclass antibodies specific for different HLA molecules.
c) Claim 22 is indefinite in the recitation of “different G4s as selected from the bank of proteins” for the same reason as is enunciated above at part “a)”.
d) Claim 23 is indefinite in the recitation of “different G4s as selected from the bank of proteins” for the same reason as is enunciated above at part “a)”.
e) Claim 23 is indefinite in the recitation of “wherein the one or more other, different G4s are selected based at least in part on a determined one or more specific immunological reactions of the tissue transplant recipient” because it is not clear what is meant.
10. No claim is allowed.
11. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641