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 .
Election/Restrictions and Claim Status
Applicants’ amendments and arguments filed 2/28/25 are acknowledged. Any objection or rejection from the 8/29/24 office action that is not addressed below is withdrawn based on the amendments.
Previously, Group 2 and SEQ ID NO:9 were elected. Since Group 2 was elected, claims 1-15 are drawn to a non-elected group. Since SEQ ID NO:9 does not include the features of claim 17, claim 17 is drawn to a non-elected species.
The elected species was found in the prior art and claims to the elected species are rejected as set forth below. Any relevant art that was uncovered during the search for the elected species is cited herein in order to advance prosecution.
Claims 1-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/27/21.
Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/6/21.
Claims 19-20 have been canceled.
Claims 16, 18 and 21-22 are being examined.
Priority
This application claims benefit of 62/826,447 03/29/2019 and is a CIP of 16/104,037 08/16/2018 which is a CON of 14/917,460 03/08/2016 PAT 10081667 which is a 371 of PCT/US14/58640 10/01/2014 which claims benefit of 61/885,300 10/01/2013.
Based on the new matter rejection set forth below, the instant claims are not fully supported by any of the documents of the previous paragraph.
Claim Rejections - 35 USC § 112
Claims were previously rejected under 112(b)/2nd. Since the claims have been amended and new claims added a newly updated rejection appears below.
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.
Claim 16, 18 and 21-22 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.
As amended, claims 16, 18 and 21-22 recites ‘as a reference’ or ‘reference ELP’. It is unclear how or if the word ‘reference’ alters the scope of the claim. It is unclear if a ‘reference ELP’ is to have certain features as compared to any other ‘ELP’. Claims are to be interpreted in light of the specification (see MPEP 2111). However, the specification does not refer to a ‘reference ELP’ or ‘as a reference’.
As amended, claims 16, 18 and 21-22 refer to ‘determining’ or ‘measuring’. Claim 16 specifically refers to ‘measuring a decrease in the distribution of the composition in the chorionic plate and increase in the distribution in the labyrinth/junctional zones’ in the context of the second ELP. The claim then refers to coupling the second ELP. With respect to measuring, any specification examples appear to relate to using rhodamine labeled polypeptides (section 00144 of the specification). It is unclear if the coupling of the second ELP is required to be a coupling of an ELP that is specifically labeled. No other method of measuring distribution has been set forth and it is unclear if specifically labeling the polypeptide is a critical feature.
Although unclear, the instant claims are given the broadest reasonable interpretation and have been interpreted such that they are enabled and 101 compliant.
Claims were previously rejected under 112a/1st. Since the claims have been amended and new claims added the rejection is updated.
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 16, 18 and 21-22 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is a ‘new matter’ rejection. Section 2163 of the MPEP states: ‘While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure’.
As amended, claims 16, 18 and 21-22 recites ‘as a reference’ or ‘reference ELP’. The phrases ‘as a reference’ and ‘reference ELP’ do not appear in the instant specification. It is unclear if a ‘reference ELP’ is to have certain features as compared to any other ‘ELP’. Although the specification does provide examples, it is unclear if such examples use a ‘reference ELP’ and it is unclear what features are required for any reference ELP. Applicants point to various figures including 12 for support. Figure 12 shows the use of ‘Free VEGF’. ‘Free VEGF’ is not an ELP. Applicants point to various figures including 17 for support. Figure 17 shows the use of ‘Free p50’. ‘Free p50’ is not an ELP. As such, there is no reason to conclude that claims 16, 18 and 21-22 are supported in the specification through express, implicit, or inherent disclosure for at least the reasons discussed above.
As amended, claims 16, 18 and 21-22 refer to ‘determining’ or ‘measuring’. Claim 16 specifically refers to ‘measuring a decrease in the distribution of the composition in the chorionic plate and increase in the distribution in the labyrinth/junctional zones’ in the context of the second ELP. The claim then refers to coupling the second ELP. With respect to measuring, any specification examples appear to relate to using rhodamine labeled polypeptides (section 00144 of the specification). However, the instant claims use much broader language. Instant claim 16 appears to encompass measuring an unlabeled ELP and determining distribution in the labyrinth/junctional zones. However, there is no adequate support for such embodiment. As such, there is no reason to conclude that claims 16, 18 and 21-22 are supported in the specification through express, implicit or inherent disclosure for at least the reasons discussed above.
Response to Arguments - 112
Applicant's arguments filed 2/28/25 have been fully considered but they are not persuasive with respect to the rejections set forth above.
Although applicants argue that the claims have been amended, the amended claims are addressed above.
Claim Rejections - 35 USC § 103
Claims were previously rejected under 103. Since the claims have been amended the rejections are updated to correspond to the instant claims.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16, 18 and 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bidwell et al. (WO 2015/051001 04-2015; ‘Bidwell’; first cited 7/15/21) in view of Dreher et al. (‘Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers’ Journal of the National Cancer Institute v98(5) March 1 2006 pages 335-344; ‘Dreher’).
Bidwell teach reducing the amount of therapeutic agent crossing a placenta in a pregnant subject and teach coupling to an ELP (abstract). Bidwell teach intra-placental distribution of ELPs and teach detection of fluorescence of rhodamine-labeled ELP in the chorionic plate and labyrinth (sections 0020, 0095 and 0099). Bidwell teach that ELP can provide advantages related to half-life (sections 0057, 0067, 00100 and 00112). Bidwell teach that ELP-VEGF had a lower plasma clearance than free VEGF (sections 0026, 00106 and 00112). Bidwell teach that the ELP fusion greatly enhances the plasma half-life and levels of therapeutic peptide and effectively prevents from entering the fetal circulation (section 00112). Bidwell teach that SynB1-ELP-p50 was administered to pregnant rats and the data shows that the fusion effectively prevents the peptide from entering fetal circulation (example 5 pages 37-38, specifically section 00112 on page 38 and figure 17) where p50 is a known agent that inhibits NFkappa-B activation (section 0028). Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2) or 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4). Bidwell teach that the fusion comprises a cell penetrating peptide (SynB1), an ELP and a NF-KB inhibitory peptide (page 10 SEQ ID NO:15) which comprises SEQ ID NO: 4 which contains 160 repeats of VPGXG. Bidwell expressly teach that synthesis involves increasing the ELP repeat size in increments (section 0089 page 30). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31). Bidwell does suggest treating diseases (claim 43) and specifically recites SEQ ID NO:9 (claim 19). Bidwell teach applications for cancer (section 0011 and claim 41).
Bidwell does not teach in a working example the elected species.
Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section). Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section). Dreher teach enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column). Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references).
It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of Bidwell based on the specific teachings and suggestions of Bidwell. Since Bidwell teach reducing the amount of therapeutic agent crossing a placenta in a pregnant subject and teach coupling to an ELP (abstract) one would have been motivated to prepare compositions and test accordingly. Since Bidwell teach applications for cancer (section 0011 and claim 41) one would have been motivated to incorporate the teachings of Dreher who teach delivery of anticancer therapeutic agents (abstract). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to optimize and test various lengths of the ELPs of Bidwell. Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2) or 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4) so one would have been motivated to make and test such polypeptides. Since Bidwell teach intra-placental distribution of ELPs and teach detection of fluorescence of rhodamine-labeled ELP in the chorionic plate and labyrinth (sections 0020, 0095 and 0099) one would have been motivated to measure the distribution. Dreher also teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Since Bidwell teach reducing the amount of therapeutic agent crossing a placenta in a pregnant subject and teach coupling to an ELP (abstract) one would have been motivated to test the conjugated therapeutic agent. Bidwell teach that SynB1-ELP-p50 was administered to pregnant rats and the data shows that the fusion effectively prevents the peptide from entering fetal circulation (example 5 pages 37-38, specifically section 00112 on page 38 and figure 17) where p50 is a known agent that inhibits NFkappa-B activation (section 0028). Further, Bidwell specifically recites SEQ ID NO:9 (claim 19) as the ELP. Thus one would have been motivated to use SEQ ID NO:9 as the ELP in the SynB1-ELP-p50 construct. Since Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2) or 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4) one would have been motivated to make such constructs. Further, since Bidwell teach that ELP-VEGF had a lower plasma clearance than free VEGF (sections 0026, 00106 and 00112) and Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section) one would have been motivated to measure the half-life and plasma clearance rate of the drug carrier. One would have had a reasonable expectation of success since the peptides and methods of making were known.
In relation to the providing a first ELP and forming a second ELP of claim 16, Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2). Bidwell teach that the peptide can have 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the determining the distribution and measuring of claim 16, Bidwell teach intra-placental distribution of ELPs and teach detection of fluorescence of rhodamine-labeled ELP in the chorionic plate and labyrinth (sections 0020, 0095 and 0099). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph).
In relation to coupling as in claim 16, Bidwell teach that the fusion comprises a cell penetrating peptide (SynB1), an ELP and a NF-KB inhibitory peptide (page 10 SEQ ID NO:15) which comprises SEQ ID NO: 4 which contains repeats of VPGXG. Bidwell expressly teach that synthesis involves increasing the ELP repeat size in increments (section 0089 page 30). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31).
In relation to ‘wherein when administered…’ of claim 16, Bidwell teach that the ELP fusion greatly enhances the plasma half-life and levels of therapeutic peptide and effectively prevents from entering the fetal circulation (section 00112).
In relation to the providing a first ELP and modifying the ELP of claim 18, Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2). Bidwell teach that the peptide can have 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract). Bidwell expressly teach that synthesis involves increasing the ELP repeat size in increments (section 0089 page 30). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31).
In relation to the measuring the half-life of claim 18, Bidwell teach that ELP can provide advantages related to half-life (sections 0057, 0067, 00100 and 00112) so one would have been motivated to measure. Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph).
In relation to the providing a first ELP and forming a second ELP of claim 21, Bidwell teach that the peptide can have 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4). Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the determining the distribution of claim 21, Bidwell teach intra-placental distribution of ELPs and teach detection of fluorescence of rhodamine-labeled ELP in the chorionic plate and labyrinth (sections 0020, 0095 and 0099).
In relation to coupling as in claim 21, Bidwell teach that the fusion comprises a cell penetrating peptide (SynB1), an ELP and a NF-KB inhibitory peptide (page 10 SEQ ID NO:15) which comprises SEQ ID NO: 4 which contains repeats of VPGXG. Bidwell teach recombinant expression of the polypeptides (section 0092 page 31).
In relation to ‘wherein when administered…’ of claim 21, Dreher recognizes that increasing the molecular weight reduced vascular permeability (so decreasing molecular weight increases permeability).
In relation to the providing a first ELP and producing a second ELP of claim 22, Bidwell teach that the peptide can have 160 repeats of VPGXG (claims 8-9 and SEQ ID NO:4). Bidwell teach that the peptide can have 32 repeats of VPGXG (claims 4-5 and SEQ ID NO:2). Bidwell teach recombinant expression of the polypeptides (section 0092 page 31). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the measuring the plasma clearance of claim 22, Bidwell teach that ELP-VEGF had a lower plasma clearance than free VEGF (sections 0026, 00106 and 00112).
In relation to the administering of claim 22, Bidwell teach that SynB1-ELP-p50 was administered to pregnant rats and the data shows that the fusion effectively prevents the peptide from entering fetal circulation (example 5 pages 37-38, specifically section 00112 on page 38 and figure 17).
In relation to any outcomes/properties recited in the claims (for example ‘for extending of claim 18’), the prior art suggest steps as claimed so the polypeptides are interpreted as suitable for the intended use.
Claims 16, 18 and 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Raucher et al. (US 2010/0022466, cited with IDS 1/21/21; ‘Raucher’) in view of Hilbert (US 2012/0213781, cited with IDS 1/21/21) in view of Loibl et al. (‘Treatment of breast cancer during pregnancy: an observational study’ Lancet Oncology v13 September 2012 pages 887-896; ‘Loibl’; first cited 7/15/21) in view of Dreher et al. (‘Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers’ Journal of the National Cancer Institute v98(5) March 1 2006 pages 335-344; ‘Dreher’).
Raucher teach the use of elastin-like polypeptides for delivery of doxorubicin (abstract and claim 5). Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2) and specifically teach Tat-ELP2-GFLG-Dox (section 0121). Raucher teach that the peptides were expressed in E. coli (section 0109). Raucher teach administration to a tumor (claim 16 and figure 1) and Raucher teach Tat-ELP2-GFLG-Dox was administered to cells and was cytotoxic by itself (figure 8b and section 0125). Raucher suggest for treating cancer (section 0001) including breast cancer (sections 0065 and 0069 and claim 9) and non-Hodgkin’s lymphoma (section 0065).
Raucher suggest administration to a subject (sections 0001 and 0036) but does not specifically recite a pregnant subject.
Hilbert teach the use of elastin like fusion peptides for therapeutic applications (abstract). Hilbert specifically teach that non-Hodgkin’s lymphoma during pregnancy is a type of cancer to be treated (section 0555). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
Loibl teach the treatment of breast cancer during pregnancy (summary on page 887) specifically those being treated with doxorubicin (page 890 2nd column first complete paragraph). Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Loibl states that on the basis of the findings that breast cancer during pregnancy could be treated as it is in non-pregnant women (page 895 Panel section interpretation). Loibl teach that the amounts of therapeutic agents can be detected in the fetus (page 895 first paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section). Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section). Dreher teach enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column). Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references).
It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of Raucher because Raucher suggest administration to a subject (sections 0001 and 0036) and suggest for treating breast cancer (sections 0065 and 0069 and claim 9). Thus one would be motivated to treat specific patient populations including those mentioned in Hilbert and Loibl. Since Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120) one would have been motivated to make such constructs. Raucher teach administration to a tumor (claim 16 and figure 1) and suggest for treating cancer (section 0001) so one would have been motivated to incorporate the teachings of Dreher who teach delivery of anticancer therapeutic agents (abstract). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to optimize and test various lengths of the ELPs of Raucher. Since Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column) one would have been motivated to measure the distribution of the administered agents. Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to test the distribution of the ELPs. Since Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section) one would have been motivated to measure the half-life. Since Dreher teach decreased rate of clearance and enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column) one would have been motivated to measure the clearance rate. One would have had a reasonable expectation of success since Raucher teach Tat-ELP2-GFLG-Dox was cytotoxic by itself (figure 8b and section 0125) and Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
In relation to the providing a first ELP and forming a second ELP of claim 16, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the determining the distribution and measuring of claim 16, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 16, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to the providing a first ELP and modifying the ELP of claim 18, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the measuring the half-life of claim 18, Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the providing a first ELP and forming a second ELP of claim 21, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the determining the distribution of claim 21, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 21, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to ‘wherein when administered…’ of claim 21, Dreher recognizes that increasing the molecular weight reduced vascular permeability (so decreasing molecular weight increases permeability).
In relation to the providing a first ELP and producing a second ELP of claim 22, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the measuring the plasma clearance of claim 22, Dreher teach decreased clearance enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column)
In relation to the administering of claim 22, Raucher teach administration to a tumor (claim 16 and figure 1).
In relation to any outcomes/properties recited in the claims (for example ‘for extending of claim 18’), the prior art suggest steps as claimed so the polypeptides are interpreted as suitable for the intended use.
Response to Arguments - 103
Applicant's arguments filed 2/28/25 have been fully considered but they are not persuasive with respect to the rejections set forth above.
Although applicants argue that the claims have been amended, the amended claims are rejected as set forth above.
Although applicants argue about the teachings of Bidwell alone, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily teach all of the claim limitations.
Although applicants argue about Raucher and Hilbert and Loibl references alone, such references are used as part of a 103 rejection that includes multiple references and as such any single reference does not necessarily anticipate the claim.
Although applicants argue that Raucher teach a sequence with a linker, instant claim 16 broadly recites ‘coupling the second ELP’ which does not exclude the presence of a linker. Claim 18 recites ‘modifying the ELP’ which does not exclude the presence of a linker. Claim 21 broadly recites ‘coupling the second ELP’ which does not exclude the presence of a linker. Claim 22 broadly recites ‘producing a second ELP’ which does not exclude the presence of a linker.
Although applicants argue that the mechanism of action is different, the active steps of the instant claims do not relate to a mechanism. The steps of the instant claims are addressed above.
Although applicants argue that the Loibl reference provides a teaching away since the present invention is focused on restricting placental drug transfer, Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). One would not recognize such fact as a teaching away. MPEP 2144 IV expressly recognizes that the reason or motivation to modify a reference can be for a different purpose and that it is not necessary for the prior art to suggest the combination to achieve the same result. In the instant case, the reason to modify the reference can be for a different purpose.
Double Patenting
Claims were previously rejected under double patenting. Since the claims have been amended the rejections are updated to correspond to the instant claims.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 16, 18 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,081,667 (667) in view of Raucher et al. (US 2010/0022466, cited with IDS 1/21/21; ‘Raucher’) in view of Hilbert (US 2012/0213781, cited with IDS 1/21/21) in view of Loibl et al. (‘Treatment of breast cancer during pregnancy: an observational study’ Lancet Oncology v13 September 2012 pages 887-896; ‘Loibl’; first cited 7/15/21) in view of Dreher et al. (‘Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers’ Journal of the National Cancer Institute v98(5) March 1 2006 pages 335-344; ‘Dreher’).
667 recites methods of administering an ELP coupled to a therapeutic agent to a pregnant subject (claim 1) where the ELP is SEQ ID NO: 9 (claim 4). 667 recites ELP with about 32 repeats (claim 6) and about 160 repeats (claim 5). 667 recites cell penetrating peptides (claim 9).
667 does not recite recombinant protein production or measuring steps.
Raucher teach the use of elastin-like polypeptides for delivery of doxorubicin (abstract and claim 5). Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2) and specifically teach Tat-ELP2-GFLG-Dox (section 0121). Raucher teach that the peptides were expressed in E. coli (section 0109). Raucher teach administration to a tumor (claim 16 and figure 1) and Raucher teach Tat-ELP2-GFLG-Dox was administered to cells and was cytotoxic by itself (figure 8b and section 0125). Raucher suggest for treating cancer (section 0001) including breast cancer (sections 0065 and 0069 and claim 9) and non-Hodgkin’s lymphoma (section 0065).
Hilbert teach the use of elastin like fusion peptides for therapeutic applications (abstract). Hilbert specifically teach that non-Hodgkin’s lymphoma during pregnancy is a type of cancer to be treated (section 0555). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
Loibl teach the treatment of breast cancer during pregnancy (summary on page 887) specifically those being treated with doxorubicin (page 890 2nd column first complete paragraph). Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Loibl states that on the basis of the findings that breast cancer during pregnancy could be treated as it is in non-pregnant women (page 895 Panel section interpretation). Loibl teach that the amounts of therapeutic agents can be detected in the fetus (page 895 first paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section). Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section). Dreher teach enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column). Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references).
It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of 667 because 667 teach methods that require ELPs and Raucher provide known methods of how to make ELPs. Since 667 recites ELP with about 32 repeats (claim 6) and about 160 repeats (claim 5) one would have been motivated to make such constructs. Since 667 teach treatments in pregnant subjects one would have been motivated to incorporate the teachings of Raucher, Loibl and Hilbert. It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of Raucher because Raucher suggest administration to a subject (sections 0001 and 0036) and suggest for treating breast cancer (sections 0065 and 0069 and claim 9). Thus one would be motivated to treat specific patient populations including those mentioned in Hilbert and Loibl. Since Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120) one would have been motivated to make such constructs. Raucher teach administration to a tumor (claim 16 and figure 1) and suggest for treating cancer (section 0001) so one would have been motivated to incorporate the teachings of Dreher who teach delivery of anticancer therapeutic agents (abstract). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to optimize and test various lengths of the ELPs of Raucher. Since Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column) one would have been motivated to measure the distribution of the administered agents. Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to test the distribution of the ELPs. Since Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section) one would have been motivated to measure the half-life. Since Dreher teach decreased rate of clearance and enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column) one would have been motivated to measure the clearance rate. One would have had a reasonable expectation of success since Raucher teach Tat-ELP2-GFLG-Dox was cytotoxic by itself (figure 8b and section 0125) and Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
In relation to the providing a first ELP and forming a second ELP of claim 16, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the determining the distribution and measuring of claim 16, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 16, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to the providing a first ELP and modifying the ELP of claim 18, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the measuring the half-life of claim 18, Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the providing a first ELP and forming a second ELP of claim 21, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the determining the distribution of claim 21, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 21, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to ‘wherein when administered…’ of claim 21, Dreher recognizes that increasing the molecular weight reduced vascular permeability (so decreasing molecular weight increases permeability).
In relation to the providing a first ELP and producing a second ELP of claim 22, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the measuring the plasma clearance of claim 22, Dreher teach decreased clearance enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column)
In relation to the administering of claim 22, Raucher teach administration to a tumor (claim 16 and figure 1).
In relation to any outcomes/properties recited in the claims (for example ‘for extending of claim 18’), the prior art suggest steps as claimed so the polypeptides are interpreted as suitable for the intended use.
Claims 16, 18 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,564,991 (991) in view of in view of Raucher et al. (US 2010/0022466, cited with IDS 1/21/21; ‘Raucher’) in view of Hilbert (US 2012/0213781, cited with IDS 1/21/21) in view of Loibl et al. (‘Treatment of breast cancer during pregnancy: an observational study’ Lancet Oncology v13 September 2012 pages 887-896; ‘Loibl’; first cited 7/15/21) in view of Dreher et al. (‘Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers’ Journal of the National Cancer Institute v98(5) March 1 2006 pages 335-344; ‘Dreher’).
911 recites administering an ELP and a therapeutic agent for a specific purpose (claim 9). 911 teach that the peptide can have 300 or 400 repeats (claims 10-11). 911 recites a targeting domain (claim 8).
911 does not recite recombinant protein production or measuring.
Raucher teach the use of elastin-like polypeptides for delivery of doxorubicin (abstract and claim 5). Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2) and specifically teach Tat-ELP2-GFLG-Dox (section 0121). Raucher teach that the peptides were expressed in E. coli (section 0109). Raucher teach administration to a tumor (claim 16 and figure 1) and Raucher teach Tat-ELP2-GFLG-Dox was administered to cells and was cytotoxic by itself (figure 8b and section 0125). Raucher suggest for treating cancer (section 0001) including breast cancer (sections 0065 and 0069 and claim 9) and non-Hodgkin’s lymphoma (section 0065).
Hilbert teach the use of elastin like fusion peptides for therapeutic applications (abstract). Hilbert specifically teach that non-Hodgkin’s lymphoma during pregnancy is a type of cancer to be treated (section 0555). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
Loibl teach the treatment of breast cancer during pregnancy (summary on page 887) specifically those being treated with doxorubicin (page 890 2nd column first complete paragraph). Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Loibl states that on the basis of the findings that breast cancer during pregnancy could be treated as it is in non-pregnant women (page 895 Panel section interpretation). Loibl teach that the amounts of therapeutic agents can be detected in the fetus (page 895 first paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section). Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section). Dreher teach enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column). Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references).
It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of 991 because 991 teach methods that require ELPs and Raucher provide known methods of how to make ELPs. Since 991 recites ELP of different lengths (claim 3) one would have been motivated to make such construct. It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of Raucher because Raucher suggest administration to a subject (sections 0001 and 0036) and suggest for treating breast cancer (sections 0065 and 0069 and claim 9). Thus one would be motivated to treat specific patient populations including those mentioned in Hilbert and Loibl. Since Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120) one would have been motivated to make such constructs. Raucher teach administration to a tumor (claim 16 and figure 1) and suggest for treating cancer (section 0001) so one would have been motivated to incorporate the teachings of Dreher who teach delivery of anticancer therapeutic agents (abstract). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to optimize and test various lengths of the ELPs of Raucher. Since Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column) one would have been motivated to measure the distribution of the administered agents. Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to test the distribution of the ELPs. Since Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section) one would have been motivated to measure the half-life. Since Dreher teach decreased rate of clearance and enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column) one would have been motivated to measure the clearance rate. One would have had a reasonable expectation of success since Raucher teach Tat-ELP2-GFLG-Dox was cytotoxic by itself (figure 8b and section 0125) and Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
In relation to the providing a first ELP and forming a second ELP of claim 16, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the determining the distribution and measuring of claim 16, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 16, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to the providing a first ELP and modifying the ELP of claim 18, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the measuring the half-life of claim 18, Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the providing a first ELP and forming a second ELP of claim 21, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the determining the distribution of claim 21, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 21, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to ‘wherein when administered…’ of claim 21, Dreher recognizes that increasing the molecular weight reduced vascular permeability (so decreasing molecular weight increases permeability).
In relation to the providing a first ELP and producing a second ELP of claim 22, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the measuring the plasma clearance of claim 22, Dreher teach decreased clearance enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column)
In relation to the administering of claim 22, Raucher teach administration to a tumor (claim 16 and figure 1).
In relation to any outcomes/properties recited in the claims (for example ‘for extending of claim 18’), the prior art suggest steps as claimed so the polypeptides are interpreted as suitable for the intended use.
Claims 16, 18 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,248,038 (038) in view of in view of Raucher et al. (US 2010/0022466, cited with IDS 1/21/21; ‘Raucher’) in view of Hilbert (US 2012/0213781, cited with IDS 1/21/21) in view of Loibl et al. (‘Treatment of breast cancer during pregnancy: an observational study’ Lancet Oncology v13 September 2012 pages 887-896; ‘Loibl’; first cited 7/15/21) in view of Dreher et al. (‘Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers’ Journal of the National Cancer Institute v98(5) March 1 2006 pages 335-344; ‘Dreher’).
038 recites administering an ELP and a therapeutic agent for a specific purpose (claim 1). 038 recites that the peptide can have 95 or 671 repeats (claims 3 and 12). 038 teach for treating cancer (claim 20).
038 does not recite recombinant protein production.
Raucher teach the use of elastin-like polypeptides for delivery of doxorubicin (abstract and claim 5). Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2) and specifically teach Tat-ELP2-GFLG-Dox (section 0121). Raucher teach that the peptides were expressed in E. coli (section 0109). Raucher teach administration to a tumor (claim 16 and figure 1) and Raucher teach Tat-ELP2-GFLG-Dox was administered to cells and was cytotoxic by itself (figure 8b and section 0125). Raucher suggest for treating cancer (section 0001) including breast cancer (sections 0065 and 0069 and claim 9) and non-Hodgkin’s lymphoma (section 0065).
Hilbert teach the use of elastin like fusion peptides for therapeutic applications (abstract). Hilbert specifically teach that non-Hodgkin’s lymphoma during pregnancy is a type of cancer to be treated (section 0555). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
Loibl teach the treatment of breast cancer during pregnancy (summary on page 887) specifically those being treated with doxorubicin (page 890 2nd column first complete paragraph). Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Loibl states that on the basis of the findings that breast cancer during pregnancy could be treated as it is in non-pregnant women (page 895 Panel section interpretation). Loibl teach that the amounts of therapeutic agents can be detected in the fetus (page 895 first paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section). Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section). Dreher teach enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column). Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references).
It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of 038 because 038 teach methods that require ELPs and Raucher provide known methods of how to make ELPs. Since 038 recites ELP of different lengths (claim 4) one would have been motivated to make such construct. Since 038 teach treatment of cancer (claim 20) one would have been motivated to incorporate the teachings of Raucher, Loibl, Hilbert and Dreher. It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of Raucher because Raucher suggest administration to a subject (sections 0001 and 0036) and suggest for treating breast cancer (sections 0065 and 0069 and claim 9). Thus one would be motivated to treat specific patient populations including those mentioned in Hilbert and Loibl. Since Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120) one would have been motivated to make such constructs. Raucher teach administration to a tumor (claim 16 and figure 1) and suggest for treating cancer (section 0001) so one would have been motivated to incorporate the teachings of Dreher who teach delivery of anticancer therapeutic agents (abstract). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to optimize and test various lengths of the ELPs of Raucher. Since Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column) one would have been motivated to measure the distribution of the administered agents. Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to test the distribution of the ELPs. Since Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section) one would have been motivated to measure the half-life. Since Dreher teach decreased rate of clearance and enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column) one would have been motivated to measure the clearance rate. One would have had a reasonable expectation of success since Raucher teach Tat-ELP2-GFLG-Dox was cytotoxic by itself (figure 8b and section 0125) and Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
In relation to the providing a first ELP and forming a second ELP of claim 16, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the determining the distribution and measuring of claim 16, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 16, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to the providing a first ELP and modifying the ELP of claim 18, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the measuring the half-life of claim 18, Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the providing a first ELP and forming a second ELP of claim 21, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the determining the distribution of claim 21, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 21, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to ‘wherein when administered…’ of claim 21, Dreher recognizes that increasing the molecular weight reduced vascular permeability (so decreasing molecular weight increases permeability).
In relation to the providing a first ELP and producing a second ELP of claim 22, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the measuring the plasma clearance of claim 22, Dreher teach decreased clearance enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column)
In relation to the administering of claim 22, Raucher teach administration to a tumor (claim 16 and figure 1).
In relation to any outcomes/properties recited in the claims (for example ‘for extending of claim 18’), the prior art suggest steps as claimed so the polypeptides are interpreted as suitable for the intended use.
Claims 16, 18 and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 11 and 23-25 of copending Application No. 16/104,037 (037) in view of in view of Raucher et al. (US 2010/0022466, cited with IDS 1/21/21; ‘Raucher’) in view of Hilbert (US 2012/0213781, cited with IDS 1/21/21) in view of Loibl et al. (‘Treatment of breast cancer during pregnancy: an observational study’ Lancet Oncology v13 September 2012 pages 887-896; ‘Loibl’; first cited 7/15/21) in view of Dreher et al. (‘Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers’ Journal of the National Cancer Institute v98(5) March 1 2006 pages 335-344; ‘Dreher’).
This is a provisional nonstatutory double patenting rejection.
037 recites administering an ELP and a therapeutic agent to a pregnant subject for a specific purpose (claim 1). 037 teach that the peptide can have at least about 5 repeats (claim 1). 037 stats that the composition does not cross the placenta (claim 1).
037 does not recite recombinant protein production.
Raucher teach the use of elastin-like polypeptides for delivery of doxorubicin (abstract and claim 5). Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2) and specifically teach Tat-ELP2-GFLG-Dox (section 0121). Raucher teach that the peptides were expressed in E. coli (section 0109). Raucher teach administration to a tumor (claim 16 and figure 1) and Raucher teach Tat-ELP2-GFLG-Dox was administered to cells and was cytotoxic by itself (figure 8b and section 0125). Raucher suggest for treating cancer (section 0001) including breast cancer (sections 0065 and 0069 and claim 9) and non-Hodgkin’s lymphoma (section 0065).
Hilbert teach the use of elastin like fusion peptides for therapeutic applications (abstract). Hilbert specifically teach that non-Hodgkin’s lymphoma during pregnancy is a type of cancer to be treated (section 0555). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
Loibl teach the treatment of breast cancer during pregnancy (summary on page 887) specifically those being treated with doxorubicin (page 890 2nd column first complete paragraph). Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Loibl states that on the basis of the findings that breast cancer during pregnancy could be treated as it is in non-pregnant women (page 895 Panel section interpretation). Loibl teach that the amounts of therapeutic agents can be detected in the fetus (page 895 first paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section). Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section). Dreher teach enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column). Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references).
It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of 037 because 037 teach methods that require ELPs and Raucher provide known methods of how to make ELPs. Since 037 teach treatments in pregnant subjects one would have been motivated to incorporate the teachings of Raucher, Loibl and Hilbert. It would have been obvious to one or ordinary skill in the art before the effective filing date to modify the teachings of Raucher because Raucher suggest administration to a subject (sections 0001 and 0036) and suggest for treating breast cancer (sections 0065 and 0069 and claim 9). Thus one would be motivated to treat specific patient populations including those mentioned in Hilbert and Loibl. Since Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120) one would have been motivated to make such constructs. Raucher teach administration to a tumor (claim 16 and figure 1) and suggest for treating cancer (section 0001) so one would have been motivated to incorporate the teachings of Dreher who teach delivery of anticancer therapeutic agents (abstract). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to optimize and test various lengths of the ELPs of Raucher. Since Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column) one would have been motivated to measure the distribution of the administered agents. Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Since Dreher teach that tumor accumulation was maximal for certain molecular weights (abstract – results section) one would have been motivated to test the distribution of the ELPs. Since Dreher teach increasing the molecular weight of a particular carrier reduced its vascular permeability and increased its plasma half-life (abstract – results section) one would have been motivated to measure the half-life. Since Dreher teach decreased rate of clearance and enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column) one would have been motivated to measure the clearance rate. One would have had a reasonable expectation of success since Raucher teach Tat-ELP2-GFLG-Dox was cytotoxic by itself (figure 8b and section 0125) and Loibl teach that any differences in infants exposed to chemotherapy were not clinically significant (page 887 section interpretation). Hilbert teach that one can readily control the molecular weight of the protein (section 0488).
In relation to the providing a first ELP and forming a second ELP of claim 16, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the determining the distribution and measuring of claim 16, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 16, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to the providing a first ELP and modifying the ELP of claim 18, Raucher teach that the ELP length can contain 150 pentapeptide repeats (ELP1) or 160 pentapeptide repeats (ELP2) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher investigated how molecular weight influences the accumulation of a drug carrier in tumors (abstract – background section). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the measuring the half-life of claim 18, Dreher teach that the molecular weight of macromolecules strongly influences plasma half-life and permeability (pages 335-336 connecting paragraph). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract).
In relation to the providing a first ELP and forming a second ELP of claim 21, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the determining the distribution of claim 21, Dreher teach that the drug carrier was labeled for imaging by confocal microscopy to determine distribution (page 337 last complete paragraph and pages 337-338 connecting paragraph). Loibl teach that the placenta filters cytotoxic agents but there is variation in transplacental passage among drugs (page 894 first paragraph of second column).
In relation to coupling as in claim 21, Raucher teach an elastin-like polypeptide with 160 repeats of the sequence XGVPG where X is V, A, G in a ratio of 1:8:7 where doxorubicin is conjugated to the sequence (i.e. Tat-ELP2-GFLG-Dox) (section 0120 and figure 2).
In relation to ‘wherein when administered…’ of claim 21, Dreher recognizes that increasing the molecular weight reduced vascular permeability (so decreasing molecular weight increases permeability).
In relation to the providing a first ELP and producing a second ELP of claim 22, Raucher teach that the ELP length can contain 160 pentapeptide repeats (ELP2) or 150 pentapeptide repeats (ELP1) (section 0120). Raucher teach that the peptides were expressed in E. coli (section 0109). Dreher teach that the results provide guidelines to optimize the use of drug carriers (page 341 last paragraph and page 342 last paragraph before references) and specifically refers to molecular weight (abstract) (where optimization includes both increasing and decreasing repeat units).
In relation to the measuring the plasma clearance of claim 22, Dreher teach decreased clearance enhanced permeability and retention effect that results in increased accumulation of macromolecules in tumors (page 335 first paragraph of 2nd column)
In relation to the administering of claim 22, Raucher teach administration to a tumor (claim 16 and figure 1).
In relation to any outcomes/properties recited in the claims (for example ‘for extending of claim 18’), the prior art suggest steps as claimed so the polypeptides are interpreted as suitable for the intended use.
Response to Arguments – double patenting
Applicant's arguments filed 2/28/25 have been fully considered but they are not persuasive with respect to the rejections set forth above.
Although applicants argue that the references are discussed above, the amended claims are rejected as set forth above and the arguments to the 103 rejection are set forth above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658
