DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-26 have been canceled. Claims 27-45 are pending and under consideration.
Claim Rejections - 35 USC § 112
Indefiniteness
Claims 27-45 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.
It is assumed the metes and bounds of chromatin insulator elements in claim 32 were well-known in the art at the time of filing as evidenced by Barkess (“Chromatin insulator elements: establishing barriers to set hetrochromatin boundaries”, Epigenomics, 2012, Vol. 4, No. 1, pg 67-80).
It is assumed the metes and bounds of chromatin insulator elements that are chicken hypersensitive site 4 (cHS4) insulator elements in claim 32 were well-known in the art at the time of filing as evidenced by Arumugam (“The 39 Region of the Chicken Hypersensitive Site-4 Insulator Has Properties Similar to Its Core and Is Required for Full Insulator Activity”, PLoS One, 2009, Vol. 4, No. 9, e6995, pg 1-15).
It is assumed the metes and bounds of a “viral transcription unit” in claim 37 were well-known.
A) The metes and bounds of a “central” polypurine “tract” in claim 27 cannot be determined. It is unclear when a sequence of a plurality of purines is “central” or a “tract”.
B) The metes and bounds of when a polyA sequence is “derived from” an SV40 late polyA signal sequence cannot be determined as required in claim 31. While a polyA sequence may be an SV40 polyA sequence, it is unclear when it is “late” or derived from an SV40 polyA signal sequence.
C) The metes and bounds of a “a chromatin insulator element comprising about 400 base pairs of the distal region of a chicken hypersensitive site-4 (cHS4) element and about 250 base pairs of a core region of a cHS4 element” in claim 32 cannot be determined. The metes and bounds of nucleic acids associated with “about 400” bp distal region of a cHS4 element are not disclosed. The metes and bounds of nucleic acids associated with “about 250” bp of a core region of a cHS4 element are not disclosed. The metes and bounds of the final structure associated with the combination of the two elements cannot be determined.
D) The metes and bound of when a cHS4 element is “inside the LTR” as required in claim 33 cannot be determined. It is unclear how an LTR can remain an LTR with a “cHS4 element” inside of it.
E) The metes and bounds of an SV40 late polyA signal sequence cannot be determined as required in claim 32. While a polyA sequence may be an SV40 polyA sequence, it is unclear when it is “late”.
F) The structure of the vector “consisting essentially of a packaging signal, the env fragment, and the 360 bp gag fragment an upstream sequence element (USE) derived from an SV40 late polyA signal sequence” in claim 34 is indefinite because the elements do not properly track with the preceding claims and because the elements are not clearly set forth. In particular, the phrase “the 360 bp gag fragment an upstream sequence element (USE) derived from an SV40 late polyA signal sequence” appears to have a grammatical error.
G) The metes and bounds of HS2, HS3, and HS4 “of the locus control regions” of a β-globin gene as required in claim 40 cannot be determined. First, the metes and bounds of “the locus control regions” of a β-globin gene cannot be determined. Next, loci are positions in space on a chromosome. They may also be considered an address on a chromosome. It is unclear how the position in space or address on a chromosome further limits the structure of the nucleic acid sequence within the genome after making the hybrid globin gene. Next, the term "locus" is singular and refers to a single nucleotide on a chromosome or gene, but the genetic modification claimed occurs over a plurality of nucleotides that change the addresses of other nucleotides within the gene. Ergo, the reference point of the "address" is unclear once the polynucleotide encoding the marker has been inserted into the gene, especially when there are multiple HS regions inserted into the hybrid gene. Overall, use of the "locus" is grammatically inappropriate, confusing, and fails to capture the structure of the hybrid globin gene.
H) The metes and bounds of a core sequence of a cHS4 insulator comprising about 250 base pairs linked to a distal element of the cHS4 comprising about 400 base pairs in claim 45 cannot be determined. It is unclear when a sequence is a “core” of a cHS4 insulator. It is unclear when a sequence is a “distal element” of a cHS4 insulator.
Claim Rejections - 35 USC § 103
A) Claims 27, 28, 30, 31, 34-44 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dull (J. Virol., 1998, Vol. 71, No. 11, pg 8463-8471) in view of Trono (20050014166), Persons (Blood, 2003, Vol. 101, pg 2175-2183).
Dull taught a SIN lentiviral vector containing
a packaging signal;
360 bp 5’ gag fragment closed by a synthetic stop codon;
700 bp of the env gene comprising an RRE and a splice acceptor; and
a transgene encoding a protein (pg 8463, 2nd col., last paragraph: “In either case, the vector itself carried the HIV-derived cis-acting sequences necessary for transcription, encapsidation, reverse transcription, and integration (2, 4, 22, 24, 29, 30, 32, 35). It thus encompassed, from the 5′ to 3′ end, the HIV 5′ LTR, the leader sequence and the 5′ splice donor site, approximately 360 bp of the gag gene (with the gag reading frame closed by a synthetic stop codon), 700 bp of the env gene containing the RRE and a splice acceptor site, an internal promoter (typically the immediate-early enhancer/promoter of human cytomegalovirus [CMV] or that of the phosphoglycerokinase gene [PGK]), the transgene, and the HIV 3′ LTR”; see also Fig. 4).
This is equivalent to a SIN lentiviral vector comprising a packaging signal, a gag gene fragment that is about 360 bp, an env gene fragment containing an RRE and a SA; and b) a transgene as required in claim 27.
Dull did not teach the vector contained a central polypurine tract (cPPT) as required in claim 27.
However, cPPTs were well-known in the art as described by Trono (paragraph 174).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a SIN lentiviral vector according to Dull using a cPPT described by Trono. Those of ordinary skill in the art at the time of filing would have been motivated to use a cPPT because Trono taught the cPPT was located in the pol gene, initiates synthesis of a downstream plus strand AND at the 3’ PPT. The result is double stranded DNA with a stable flap of 99 nucleotides that facilitates nuclear import. It is the basis for their ability to replicate in non-dividing cells (para 74).
The combined teachings of Dull and Trono did not teach the transgene encoded γ-globin as required in claim 27.
However, Persons taught a SIN lentiviral vector encoding γ-globin (Fig. 1).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a SIN lentiviral vector comprising the elements described by Dull and the cPPT described by Trono wherein the transgene encoded γ-globin as described by Persons. Those of ordinary skill in the art at the time of filing would have been motivated to replace the transgene of Dull with the γ-globin coding region for gene therapy as described by Persons.
Those of ordinary skill in the art would have had a reasonable expectation of successfully adding the cPPT element as evidenced by Trono who used it in various vectors. Those of ordinary skill in the art would have had a reasonable expectation of successfully making the transgene of Dell a γ-globin coding sequence as evidenced by Persons who used a γ-globin coding sequence in a SIN lentiviral vector for gene therapy.
Claim 40 has been included because Persons taught the vector contained HS2, HS3, and HS4 chromatin insulator elements (Fig. 1, bottom three panels).
Claim 27, 35, 39 have been included because Persons taught a γ-globin coding sequence (Fig. 1A).
Claim 37 has been included because Persons taught the γ-globin coding sequence was in reverse orientation of the 5’ and 3’ LTRs and the HS2, HS3, and HS4 elements (Fig. 1A, see also the caption).
Persons used β-spectrin and α-globin promoters (Fig. 1 caption). This is a “promoter” as required in claim 38 because it is specific to cells that express spectrin and globin.
Persons transduced bone marrow cells with the vector which is equivalent to the host cell in claims 42-43.
Persons transduced bone marrow cells with the vector which is equivalent to transfecting a host cell as required in claim 44.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
B) Claim 29 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dull (J. Virol., 1998, Vol. 71, No. 11, pg 8463-8471) in view of Trono (20050014166), Persons (Blood, 2003, Vol. 101, pg 2175-2183), Baum (20070048285) as applied to claims 27, 28, 30, 31, 34-44 and further in view of Schambach (Mol. Therap., 2007, Vol. 15, No. 6, pg 1167-1173).
The combined teachings of Dull, Trono, Persons, and Baum taught a SIN lentiviral vector containing
a) a backbone containing cis elements consisting essentially of:
a packaging signal;
360 bp 5’ gag fragment closed by a synthetic stop codon;
700 bp of the env gene comprising an RRE and a splice acceptor; and
a cPPT element;
a 3’ LTR comprising an exogenous polyA sequence downstream of the endogenous polyA sequence;
and
b) a transgene encoding γ-globin
for reasons cited above.
The combined teachings of Dull, Trono, Persons, and Baum did not teach exogenous polyA sequence was a bovine growth hormone (bGH) polyA sequence as required in claim 29.
However, Schambach taught polyA signal from bovine growth hormone (bGH) was strong (Figure 3C; pg 1168, col. 2, “USE improves transcriptional termination of gamma-retroviral SIN vectors”).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a SIN vector as described by the combined teachings of Dull, Trono, Persons, and Baum using the bGH polyA sequence described by Schambach. Those of ordinary skill in the art at the time of filing would have been motivated to modified 3’ LTR of Baum to experience the improved expression observed by Schambach using the bGH polyA sequence.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
D) Claims 32, 33, 45 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dull (J. Virol., 1998, Vol. 71, No. 11, pg 8463-8471) in view of Trono (20050014166), Persons (Blood, 2003, Vol. 101, pg 2175-2183), Rivella (J. Virol., 2000, Vol. 74, pg 4679-4687) as applied to claims 27, 28, 30, 31, 34-44 and further in view of Recillas-Targa (BioEssays, 2004, Vol. 26, pg 796-807).
The combined teachings of Dull, Trono, Persons, and Rivella taught a SIN lentiviral vector containing
a) a backbone containing cis elements consisting essentially of:
a packaging signal;
360 bp 5’ gag fragment closed by a synthetic stop codon;
700 bp of the env gene comprising an RRE and a splice acceptor; and
a cPPT element;
HS2, HS3, cHS4 chromatin insulator elements (Fig. 10A of Persons + teachings of Rivella); and
b) a transgene encoding γ-globin
for reasons cited above.
The combined teachings of Dull, Trono, Persons, and Rivella did not teach the cHS4 element had a 250 bp core linked to a 400 bp distal cHS4 element as required in claims 32, 33, 45.
However, Recillas-Targa taught a SIN vector with a cHS4 element with a 250 bp core linked to a 400 bp distal cHS4 element (pg 797, Fig. 1A).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a SIN vector as described by the combined teachings of Dull, Trono, Persons, and Rivella using the cHS4 element described by Recillas-Targa. Those of ordinary skill in the art at the time of filing would have been motivated to replace the cHS4 element of Rivella with the to protect the transgene against chromatin position effects as described by Recillas-Targa in the abstract.
Replacing the HS4 element of Persons with the cHS4 element would put it in the 3’ LTR as required in claim 33.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights