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 .
Claims 2-4, 19, 20, 22-25 have been canceled. Claims 1, 5-18, 21 are pending.
Election/Restrictions
Applicant’s election of Group I, claims 1-9, in the reply filed on 10-8-25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 10-18, 21 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10-8-25.
Claims 1, 5-9 are under consideration.
Applicant's arguments filed 5-28-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation
It is assumed the metes and bounds of “non-obese diabetic (NOD)” mice in claim 1 were well-known.
Claim Objection
The phrase “human histocompatibility complex (MHC)” is missing the word “major” for the abbreviation “MHC”. It should be ---“major histocompatibility complex (MHC)”
Claim Rejections - 35 USC § 112
Written description
Claims 1, 5-9 remain 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.
Withdrawn rejections
The rejection regarding the mouse having the alleles and nucleic acids as broadly claimed has been withdrawn because the claim has been limited to a mouse whose genome comprises inactivated genes and nucleic acid sequences encoding exogenous proteins, wherein the mouse does not express proteins encoded by the inactivated protein and expresses the exogenous proteins.
The rejection regarding a “NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ” mouse “comprising an inactivated mouse Flt3 allele; a nucleic acid encoding human IL3; a nucleic acid encoding human GM-CSF; a nucleic acid encoding human SCF; and a nucleic acid encoding HLA-A2/H2-D/B2M” as required in claim 2 has been withdrawn because the claim has been canceled.
The rejection regarding transplanting human CD45+ hematopoietic progenitor cells, wherein “lung tissue of the mouse comprises human CD3+ T-cells and HLA-DR+CD11c+ dendritic cells” in claim 8 has been withdrawn in view of pg 14, lines 17-20.
Pending rejections
A) The specification lacks written description for a nucleic acid encoding “alph1 and alpha2 binding domains of a human histocompatility complex (MHC) class I HLA-A2.1 allele covalently linked to human B2M [B2-microglubulin] and alpha3 (HLA-A2/H2-D/B2M) and cytoplasmic and transmembrane domains of murine H2-Db” as required in claim 1.
Claim 1 is drawn to a non-obese diabetic (NOD) mouse whose genome comprises:
a) an inactivated mouse Prkdc allele, an inactivated mouse IL2rg allele, and an inactivated mouse Flt3 allele, wherein the mouse does not express functional mouse PRKDC, IL2RG, or FLT3 protein; and
b) a transgene encoding human granulocyte/macrophage-stimulating factor (GM-CSF), a transgene encoding human stem cell factor (SCF), a transgene encoding human interleukin-3 (IL3) and a transgene encoding alphal and alpha2 binding domains of a human histocompatibility complex (MHC) class I HLA-A2.1 allele covalently linked to human B2M and alpha3 (HLA- A2/H2-D/B2M), cytoplasmic and transmembrane domains of murine H2-Db, wherein the mouse expresses human IL3, human GM-CSF, human SCF, and HLA-A2/H2-D/B2M.
The specification is limited to a genetically modified mouse whose genome comprises i) an inactivated Prkdc allele, ii) an inactivated IL2rg allele, iii) an inactivated Flt3 allele, iv) a nucleic acid sequence encoding human IL3, v) a nucleic acid sequence encoding human GM-CSF, vi) a nucleic acid sequence encoding human SCF, and vii) a nucleic acid sequence encoding HLA-A2/H2-D/B2M, wherein the mouse does not express functional PRKDC, IL2rg, or Flt3 and functionally expresses human IL3, human GM-CSF, human SCF, and HLA-A2/H2-D/B2M. The specification does not correlate a mouse whose genome comprises the genetic modification to a mouse with only one or a few cells with the genetic modification. Accordingly, the concept lacks written description other than a genetically modified mouse whose genome comprises i) an inactivated Prkdc allele, ii) an inactivated IL2rg allele, iii) an inactivated Flt3 allele, iv) a nucleic acid sequence encoding human IL3, v) a nucleic acid sequence encoding human GM-CSF, vi) a nucleic acid sequence encoding human SCF, and vii) a nucleic acid sequence encoding HLA-A2/H2-D/B2M, wherein the mouse does not express functional PRKDC, IL2rg, or Flt3 and functionally expresses human IL3, human GM-CSF, human SCF, and HLA-A2/H2-D/B2M.
A “nucleic acid” does not “encode” an [HLA-A2.1] “allele” as claimed; nucleic acids encoding proteins, not alleles. The phrase mixes nucleic acid and amino acid language. The domains of murine H2-Db as claimed are listed after the abbreviation HLA-A2/H2-D/B2M which does not make sense. Moreover, it is unclear how/when HLA-A2 is covalently linked to H2-D and B2M. While a nucleic acid encoding B2M may be operably linked to a nucleic acid encoding 1α and 2α binding domains of an HLA-A2, β2m is not “covalently linked” to 1α and 2α binding domains of an HLA-A2 gene as claimed. Accordingly, the phrase lacks written description.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive because the HLA-A2/H2D/B2M limitations in claim 48 erroneously mix nucleic acid and amino acid language.
B) The specification lacks written description for a mouse containing CD45+ expressing a detectable level of any HLA-A2 at 4 weeks of age as required in claim 5 because it does not have a nexus with a mouse comprising a nucleic acid encoding [α1 and α2 domains of] HLA-A2.1 in claim 1. The concept of any HLA-A2 in claim 5 is broader HLA-A2.1 in claim 1 because it is the genus that contains the species of HLA-A2.1. The concept also lacks written description because claim 1 says the 3α cytoplasmic and transmembrane domains are endogenous H2-Db, so the mouse cannot express fully human HLA-A2 as encompassed by claim 5. Accordingly, claim 5 appears broader than claim 1 and lacks written description.
Response to arguments
Applicants argue claim 5 is narrower. Applicants’ argument is not persuasive because the HLA-A2 in claim 5 is broader than HLA-A2.1 in claim 1. Claim 5 encompasses expressing fully human HLA-A2 which cannot occur in claim 1 because α3 binding domain of mouse H2-Db is part of the MHC molecule.
C) The specification lacks written description for a mouse that contains human CD19+ B-cells, CD33+ myeloid cells, and CD3+ T-cells as required in claim 7. Support has not been provided and none can be found. Therefore, the concept lacks written description.
Response to arguments
Applicants argue claim 7 has written description. Applicants’ argument is not persuasive. Support has not been provided and none can be found.
D) The specification lacks written for any mouse that has HLA-A2+ thymic epithelial cells as broadly encompassed by claim 9. The claim encompasses a mouse in which HLA-A2 is specifically expressed only in thymic epithelial cells as well as a mouse in which HLA-A2 is ubiquitously expressed. The specification is limited to a transgenic mouse whose genome comprises a nucleic acid sequence encoding HLA-A2/H2D/B2M, wherein the mouse ubiquitously expresses the HLA-A2/H2D/B2M. The specification does not contemplate the thymic epithelial cells express HLA-A2/H2D/B2M, so specifically claiming that now is after the fact and lacks written description in the original disclosure. The specification does not correlate ubiquitous presence of the nucleic acid encoding HLA-A2/H2D/B2M to tissue-specific presence of the nucleic acid only in thymic epithelial cells as broadly encompassed by claim 9. The specification does not correlate ubiquitous expression of HLA-A2/H2D/B2M to tissue-specific expression only in thymic epithelial cells as broadly encompassed by claim 9. Accordingly, the concept lacks written description.
Response to arguments
Applicants argue the examiner has improperly limited claim 9. Applicants’ argument is not persuasive. The specification is limited to a transgenic mouse whose genome comprises a nucleic acid sequence encoding HLA-A2/H2D/B2M, wherein the mouse ubiquitously expresses the HLA-A2/H2D/B2M. The specification does not contemplate the thymic epithelial cells express HLA-A2/H2D/B2M as required in claim 9, so specifically claiming that now is after the fact and lacks written description in the original disclosure.
Indefiniteness
Claims 1, 5-9 remain 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.
Pending rejections
The rejection regarding the phrase “NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ” mouse “comprising an inactivated mouse Flt3 allele; a nucleic acid encoding human IL3; a nucleic acid encoding human GM-CSF; a nucleic acid encoding human SCF; and a nucleic acid encoding HLA-A2/H2-D/B2M” in claim 2 has been withdrawn because the claim has been canceled.
The rejection regarding the concept of a nucleic acid encoding HLA-A2/H2-D/B2M being a “transgene” in claim 3 has been withdrawn because the claim has been canceled.
Withdrawn rejections
A) The concept of a nucleic acid encoding “alph1 and alpha2 binding domains of a human histocompatility complex (MHC) class I HLA-A2.1 allele covalently linked to human B2M [B2-microglubulin] and alpha3 (HLA-A2/H2-D/B2M) and cytoplasmic and transmembrane domains of murine H2-Db” in claim 1 can makes the claim indefinite. The phrase mixes nucleic acid and amino acid language and appears to covalently link a nucleic acid to an HLA binding domain; this concept is not within the realm of science, logic, or legal clarity. While a nucleic acid encoding B2M may be operably linked to a nucleic acid encoding 1α and 2α binding domains of an HLA-A2, but it is not covalently linked to 1α and 2α binding domains of an HLA-A2 gene as claimed. Accordingly, those of skill would not be able to determine when they were infringing on the claim.
B) The concept of the mouse expressing a detectable level of any HLA-A2 as required in claim 5 does not have a nexus with a mouse comprising a nucleic acid encoding an MHC that is HLA-A2.1 as required in claim 1. This makes the claim indefinite. The concept in claim 5 is broader than the nucleic acid encoding HLA-A2/H2-D/B2M in claim 1 because it encompasses a nucleic acid encoding a fully human HLA-A2 including the cytoplasmic and transmembrane domains. But claim 1 says the 3α cytoplasmic and transmembrane domains are endogenous H2-Db, so the mouse cannot express fully human HLA-A2 as encompassed by claim 5. Accordingly, claim 5 is broader than claim 1 which makes the claim indefinite.
Claim Rejections - 35 USC § 103
Claims 1 and 5 remain rejected under 35 U.S.C. 103 as being unpatentable over Shultz (Mammalian Genome, 2019, Vol. 30, pg 123-142).
Shultz taught SGM3F mice (NOD.Cg-Prkdcscid Il2rg -Flt3 (CMV-IL3, CSF, KITLG)) (pg 126, Table 1, items 10 and 11) and HLA-A0201 transgenic mice (NSG-HLA-A2 (HHD)) (pg 127, Table 1, item 5).
Shultz did not teach crossing SGM3F mice with HLA-A0201 as described by applicants on pg 14, lines 1-10.
However, Shultz taught both types of mice and taught crossing SGM3F mice with other mice, i.e. NSG-Tg(CSF1) mice (pg 130, col. 1, last para).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to cross the SGM3F mouse as described by Shultz using the HLA-A0201 mouse of Shultz. Those of ordinary skill in the art at the time of filing would have been motivated to do so to impart expression of human HLA-A0201 in the mouse thereby making it even more humanized. In the reverse, those of ordinary skill in the art at the time of filing would have been motivated to express human IL3, CSF, and GM-CSF in the HLA-A0201 mouse for immune response research.
The bone marrow cells of the mouse inherently MUST express CD45 by the age of 4 weeks as required in claim 5 because they are obtained by crossing the same mice used by applicants (pg 14, lines 1-10).
Response to arguments
Applicants argue there is no rationale or motivation to choose or the genes claimed. Applicants’ argument is not persuasive for reasons set forth above.
Applicants argue the mouse has an unpredicted phenotype (pg 11). Applicants’ argument is not persuasive. The argument fails to begin with what was expected, fails to take secondary considerations into account, and fails to compare what was expected with applicants’ results.
Applicants point to Fig. A which discusses NSG mice. That is not what was expected because it does not relate to the NOD.Cg-Prkdcscid Il2rg -Flt3 (CMV-IL3, CSF, KITLG)) or HLA-A0201 transgenic mice described by Shultz.
Applicants point to Fig. B which shows results in hSGM3F-A2 mice. That is not what was expected because they are not the NOD.Cg-Prkdcscid Il2rg -Flt3 (CMV-IL3, CSF, KITLG)) or HLA-A0201 transgenic mice described by Shultz and they are not applicants’ results because they are not mice expressing hIL3, hGMCSF, hSCF, and HLA-12/H2-D/B2M as required in claim 1.
Applicants point to Fig. C which shows results in hSGM3F-A2 mice. That is not what was expected because they are not the NOD.Cg-Prkdcscid Il2rg -Flt3 (CMV-IL3, CSF, KITLG)) or HLA-A0201 transgenic mice described by Shultz and they are not applicants’ results because they are not mice expressing hIL3, hGMCSF, hSCF, and HLA-12/H2-D/B2M as required in claim 1.
Applicants point to Fig. D which shows results in hSGM3F-A2 mice. That is not what was expected because they are not the NOD.Cg-Prkdcscid Il2rg -Flt3 (CMV-IL3, CSF, KITLG)) or HLA-A0201 transgenic mice described by Shultz and they are not applicants’ results because they are not mice expressing hIL3, hGMCSF, hSCF, and HLA-12/H2-D/B2M as required in claim 1.
Claims 6-9 remain rejected under 35 U.S.C. 103 as being unpatentable over Shultz (Mammalian Genome, 2019, Vol. 30, pg 123-142) as applied to claims 1-5 above, and further in view of Matsumura (Exp. Hematology, 2003, Vol. 31, No. 9, pg 789-797), Traggiai (Science, 2004, Vol. 304, No. 5667, pg 104-107), Aspord (J. Exp. Med, 2007, Vol. 204, No. 5, pg 1037-1047), Pedroza-Gonzalez (J. Exp. Med., 2011, Vol. 208, No. 3, pg 479-490), Wu (Cancer Immunol. Res., 2014, Vol. 2, No. 5, pg 487-500), Wu (Cancer Res., 2018, Vol. 78, No. 18, pg 5243-5258), and Yu (Blood, 2008, Vol. 112, No. 9, pg 3671-3678).
Shultz obviated the mouse of claim 1 for reasons set forth above.
Shultz did not teach administering human HPCs to the mouse as required in claim 6.
However, it was well-known to irradiate a humanized mouse and administer human CD45+ HPCs to humanized mice as described by Matsumura, Traggiai, Aspord, Pedroza-Gonzalez, Wu, Wu, and Yu (see materials and methods for each). Applicants acknowledge their contribution to administering human HPCs on pg 1, lines 17-25, of the specification.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to obtain the mouse of claim 1 by crossing the SGM3F and HLA-A0201 mice described by Shultz and administer human HPCs as described by Matsumura, Traggiai, Aspord, Pedroza-Gonzalez, Wu, Wu, and Yu. Those of ordinary skill in the art at the time of filing would have been motivated to administer HPCs to make the mice more humanized, especially when the mouse has been given a human tumor.
Claim 7 has been included because Matsumura, Traggiai, Aspord, Pedroza-Gonzalez, Wu, Wu, and Yu taught the HPCs were obtained from fetal liver, cord blood, or bone marrow and comprise a mixed population of CD19+ B-cells, CD33+ myeloid cells, and CD3+ T-cells.
Claim 8 has been included because Matsumura, Traggiai, Aspord, Pedroza-Gonzalez, Wu, Wu, and Yu taught the HPCs were obtained from fetal liver, cord blood, or bone marrow and comprise CD3+ T-cells and HLA-DR+CD11c+ dendritic cells.
Claim 9 has been included because Matsumura, Traggiai, Aspord, Pedroza-Gonzalez, Wu, Wu, and Yu taught the HPCs were HLA-A2+. The thymic epithelial cells of the mouse are HLA-A2+ because they were obtained from HLA-A0201 mice.
Response to arguments
Applicants point to previous arguments which are not persuasive for reasons set forth above.
Conclusion
No claim is allowed.
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.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
If attempts to reach the examiner are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on 571-272-2914.
The official fax number for this Group is (571) 273-8300.
Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights