DETAILED ACTION
Claims 1-2, 6-13 and 16-33 are pending with claims 1-2, 6-8 and 16-33 examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20180360994A1, Published 12/20/2018.
Maintained Prior Art Rejections
Claim(s) 1-2, 6, 16,19-20, 23-25 and 28 remain rejected under 35 U.S.C. 102 (a) (1)/(a)(2) as being anticipated by Angel et al. (WO2014071219A1, Filed 11/1/2013, Published 5/8/2014) is maintained. Applicant’s argument will be addressed following maintained rejection.
Claim(s) 7-8, 21-22, 26 and 29-33 remain rejected under 35 U.S.C. 103 as being unpatentable over Angel et al. (WO2014071219A1, Filed 11/1/2013, Published 5/8/2014) as applied to claims 1-2, 6, 16,19-20,23-25 and 28 and further in view of Prasad et al. (PgPub US20190112358A1, Filed 11/13/2015) and Zhang et al. (PgPub US20140179770A1, Published 6/26/2014). Applicant’s argument will be addressed following maintained rejection.
Claims 1-2, 6-8 and 16-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 6-8 and 16-33 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The rejection is copied below for Applicant’s convenience.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue.’ Not ‘experimentation;” (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Independent claim 1 is drawn to a method for killing cancer cells in an animal, the method comprising induction of preferential killing of cancer cells that comprise at least one DNA sequence, which is not present in healthy cells of said animal, by administering 1) an effective amount of at least one expression vector, wherein each of said at least one expression vector comprise a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence, and which comprise (s) a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when it is bound to said recognition molecule, or 2) an effective amount of at least one first expression vector, wherein each of said at least one first expression vector comprises a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence(s), and an effective amount of at least one second expression vector, which comprises a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, or 3) an effective amount of at least one recognition molecule that specifically recognizes at least one of said at least one DNA sequence and an effective amount of at least one molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, or 4) an effective amount of at least one expression vector, which comprises a nucleic acid sequence encoding a recognition molecule that specially recognizes at least one of said at least one DNA sequence and an effective amount of at least one second molecule that selectively disrupts DNA comprising sat at least one DNA sequence when being bound to said recognition molecule, or 5) an effective amount of at least one recognition molecule that specially recognizes at least one of said at least one DNA sequence an dan effective amount of at least one expression vector, which comprises a nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising at least one DNA sequence when being bound to said recognition molecule, wherein administration of said vector (s) and/or molecules (s) defined in any one of 1-5 results in disruption of nucleic acid molecules that comprise said at least one DNA sequence to such a degree that said cancer cells are lethally damaged due to introduction of multiple disruptions of the genome of said cancer cells and/or due to deletion of multiple base pairs of the genome of said cancer cells.
Independent claim 20 is drawn to a method for killing cancer cells in an animal, the method comprising induction of preferential killing of cancer cells that comprise at least one DNA sequence, which is not present in healthy cells of said animal, by administering 1) an effective amount of at least one expression vector, wherein each of said at least one expression vector comprise a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence, and which comprise (s) a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when it is bound to said recognition molecule, or 2) an effective amount of at least one first expression vector, wherein each of said at least one first expression vector comprises a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence, and an effective amount of at least one second expression vector, which comprises a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, or 3) an effective amount of at least one recognition molecule that specifically recognizes at least one of said at least one DNA sequence and an effective amount of at least one molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, or 4) an effective amount of at least one expression vector, which comprises a nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence and an effective amount of at least one second molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, or 5) an effective amount of at least one recognition molecule that specifically recognizes at least one of said at least one DNA sequence and an effective amount of at least one expression vector, which comprises a nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, wherein administration of said vector(s) and/or molecule(s) defined in any one of steps 1-5 results in disruption of nucleic acid molecules that comprise said at least one DNA sequence to such a degree that said cancer cells are killed or neutralized and wherein the animal is not exposed to any recognition molecule that recognizes the animal's autologous DNA in healthy cells.
Independent claim 21 is drawn to a method of killing cancer cells in an animal, the method comprising induction of preferential killing of cancer cells that comprise at least one DNA sequence, which is not present in in healthy cells of said animal, by administering 1) an effective amount of at least one expression vector, wherein each of said at least one expression vector comprise a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence, and which comprise(s) a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when it is bound to said recognition molecule, or 2) an effective amount of at least one first expression vector, wherein each of said at least one first expression vector comprises a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence(s), and an effective amount of at least one second expression vector, which comprises a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, wherein the recognition molecule is a crRNA and wherein said molecule that selectively disrupts said at least one DNA sequence when being bound to said recognition molecule is a CRISPR-associated protein (Cas), wherein administration of said vector(s) and/or molecule(s) defined in 1 or 2 results in disruption of nucleic acid molecules that comprise said at least one DNA sequence to such a degree that said cancer cells are lethally damaged due to introduction of multiple disruptions of the genome of said cancer cells and/or due to deletion of multiple base pairs of the genome of said cancer cells.
Independent claim 22 is drawn to a method of killing cancer cells in an animal, the method comprising induction of preferential killing of cancer cells that comprise at least one DNA sequence, which is not present in healthy cells of said animal, by administering 1) an effective amount of at least one expression vector, wherein each of said at least one expression vector(s) comprise a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence(s), and which comprise(s) a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when it is bound to said recognition molecule, or 2) an effective amount of at least one first expression vector, wherein each of said at least one expression vector(s) comprise(s) a first nucleic acid sequence encoding a recognition molecule that specifically recognizes at least one of said at least one DNA sequence(s), and an effective amount of at least one second expression vector, which comprises a second nucleic acid sequence encoding a molecule that selectively disrupts DNA comprising said at least one DNA sequence when being bound to said recognition molecule, wherein the recognition molecule is a crRNA and wherein said molecule that selectively disrupts said at least one DNA sequence when being bound to said recognition molecule is a CRISPR-associated protein (Cas), wherein administration of said vector(s) and/or molecule(s) defined in 1 or 2 results in disruption of nucleic acid molecules that comprise said at least one DNA sequence to such a degree that said cancer cells are killed or neutralized and wherein the animal is not exposed to any recognition molecules that recognizes the animal’s autologous DNA in healthy cells.
Amount of Direction Provided by Inventor/Working Examples: Starting at para. 112 of the PgPub, the specification details a ‘Bioinformatics Proof-of-Concept’ experiment which is illustrated in Fig. 1, copied below.
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Continuing, starting at para. 114 of the specification, Inventors state the input parameters for the computer system are DNA sequences from a group of cells, where said cells represent healthy tissue, and DNA sequences from a group of cells, where said cells represent malignant tissue in this experiment. The specification notes that the following algorithm could be supplied with input parameters from virus-infected cells and cells of a pathogenic organism. Continuing, the specification adds that the sequencing data could be whole genome, partial and/or deep DNA or RNA sequencing. First the PAM sequences of the healthy, or targeted cells, are identified using KMP (Knuth-Morris-Pratt) text search. The PAM sequence in this experiment represented the prospective use of Crispr-Cas9 and was thus 5′-NGG-3′. The PAM sequences, including the following or preceding DNA nucleotides with a length of the desired complementary recognition molecule, e.g. Crispr RNA, are stored in list form for later comparison. A trial run was executed using a custom algorithm made with the BioPython open source project and a chromosome 2 sample from a healthy and cancerous genome from the same individual found in AWS 1000 genomes project's database. Thereafter, the chromosome 2 sample sequences were inserted into their own respective Set (or Bag) data structure. The Set allows for duplicate values, such that more occurring sequences are not ignored, and can take part in a partial match analysis. A Set data structure is used for its constant O (1) runtime, essential for larger DNA sequences. As the third step, the two respective sets are computed into a third result set with a subtract (or difference) operation. The difference operation, results in a set of complementary recognition molecules, unique to the cancer cell to be targeted, and not existing in the healthy cell. In the conducted experiment out of 230 million nucleotides, including overlapping duplicates, 8 million potential targets were identified with the PAM occurring at variable positions within the target sequence.
Finally, the specification notes that further analysis can then be performed on the resulting set of sequences, unique to the cancer cell, or healthy cell, if desired, such as ranking of their uniqueness, ranking of target sequences that correlate with targets within sequences known to correspond with parts of the exome, ranking of the targets based on their predictive activity scorer, such as via the SgRNA Scorer 1.0; the ranking of the targets further optimized based on their usability for e.g. designing LNA, ranking based on their viability to be expressed in an specific vector, e.g. an adeno-associated virus or another vector format that can provide cellular presence of the recognition and effector molecules.
At issue for the purposes of the instant rejection is that Applicant is claiming a method of killing cancer cells but fails to provide an in vitro or an in vivo example showing of such. At best, Applicant provides a prophetic example of a computational approach to designing CRISPR RNAs- which alongside tracrRNA form guide RNAs. Although the lack of a working example does not automatically render a claimed invention non-enabling, per MPEP 2164.02, a prophetic example describes an embodiment of the invention based on predicted results rather than work actually conducted or results actually achieved. However, the computational approach to designing the CRISPR RNA example of the specification is materially unrelated to the claims under consideration. This is because (1) none of the claims under consideration require the use of a computer and/or algorithm and most glaringly, (2) the prophetic example does not kill cancer cells in any measurable manner whatsoever.
In sum, the specification is wholly inadequate in providing information relevant to the claimed invention such that one of ordinary skill in the art could practice the claimed method and/or produce the claimed results without undue experimentation. The MPEP states that “information contained in the disclosure of an application must be sufficient to inform those skilled in the relevant art how to both make and use the claimed invention" (MPEP 2164.01 c). Emphasizing the need for a specification to teach how to make and use the claimed invention, a later decision invalidated claims finding the breadth of enablement was not commensurate in scope with the claims, stating the teachings set forth in the specification provided no more than a ''plan" or "invitation" for those of skill in the art to experiment using the technology ... (In Enzo Biochem, Inc. v. Ca/gene, Inc., 188 F.3d 1362, 52 USPQ2d 1129 (Fed. Cir. 1999)).
While the specification need not teach what is well known in the art, the specification "cannot rely upon knowledge of one skilled in the art to supply information that is required to enable the novel aspect of the claimed invention when the enabling knowledge is in fact not known in the art" (ALZA Corp. v. Andrx Pharms., LLC, 603 F.3d 935, 941, 94 USPQ2d 1823, 1827 (Fed. Cir. 2010)). Previously, the Federal circuit stated "protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. Tossing out the mere germ of an idea does not constitute enabling disclosure (Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361 (Fed. Cir. 1997)).
The State of the Prior Art: Providing background, Xing and Meng (Acta Pharmacologica Sinica volume 41, pages 583–587 (2020),) teach CRISPR-Cas9 system evolved as an immune defense against foreign bacteriophage or plasmid infection in bacteria or archaea. Exogenous DNA or RNA fragments are identified and recorded by integrating a repeat-spacer array into CRISPR. Then, the CRISPR precursor is transcribed and processed into mature CRISPR-derived RNA (crRNA). After hybridization between the crRNA spacer and complementary invasive nucleotide sequences, double-strand breaks (DSBs) adjacent to the protospacer adjacent motif (PAM) are made by the cas endonuclease. The DSBs are then repaired via nonhomologous end joining (NHEJ) and homology directed repair (HDR), which directly result in end joining, base insertion and deletion or directional mutation by using the homologous repair template (Pg. 583, Col. 2, para. 1). Continuing, Xing and Meng teach tumor cells carry a wide range of genetic mutations that play important roles in oncogenesis and tumor evolution (Pg. 584, Col. 1, para. 1). Elaborating on this point, Martinez-Lage et al. (Nature Communications volume 11, Article number: 5060 (2020)) noted that unlike other genetic diseases such as Duchenne muscular dystrophy or cystic fibrosis, cancer development involves several genetic mutations that can deregulate multiple genes. In the context of cancer gene therapy, Martinez-Lage teach that it is clear that targeting a single gene is often insufficient to eliminate cancer cells (Pg. 2, Col. 1, para. 1). As such, it would be tempting to use multiple guide RNAs to target multiple genes. The use of multiple guide RNAs, alongside a Cas protein, to target loci within a genome is known as multiplexing. However, McCarty et al. (Nature Communications Vol. 11, Number: 1281 (2020)) highlights the problems associated with this technique. Indeed, McCarty lists: (1) difficulties in creating long arrays of gRNAs, and in predicting how these gRNAs will behave in living cells, (2) emergence of undesired chromosomal rearrangements using CRISPR multiplexing to cut multiple genetic loci at once and (3) as the number of gRNAs in a cell scales, they must compete for a dwindling ‘pool’ of endonucleases. With respect (3) McCarty adds that “This competition, in turn, alters the efficiency of every gRNA, an effect called retroactivity. Further, McCarty notes that while synthetic biologists strive for modularity by combining many individually characterized genetic parts together, the interconnections between these parts often result in unpredictable outputs (Pg. 9 ‘Insights and challenges of multiplexed Crispr technologies’). Particularly problematic is that Applicant has not shown how the computational-derived gRNAs behave in living cells. As noted in McCarty, there exists a significant unpredictability in their behavior in living cells.
Each of the cited references cast significant doubt on the claimed methods. As noted in Martinez-Lage, cancer is unique in that it involves several genetic mutations that can deregulate multiple genes. A CRISPR technique that allows for targeting multiple genes (multiplexing) is plagued with uncertainty and limited understanding. The as-filed specification fails to acknowledge the known problems associated with targeting multiple genes. When taken as a whole, and as understood by a person of ordinary skill in the art, it is clear that the specification is wholly inadequate in enabling the claimed inventions. The specification sheds very little light, if any, on the known problems associated with CRISPR technology. Consequently, the specification fails to address how to overcome these known problems. Therefore, based on these considerations, it would be reasonable to conclude that it would require an undue amount of experimentation in order to treat kill cancer cells, as claimed, using the specification as guide.
Burrowing down to a granular level, Daisy et al. (Molecular Biotechnology volume 63, pages93–108 (2021)) opines “Every advantage has its own disadvantage” and although CRISPR-based systems have laid a profound podium for cancer treatment, there are a lot of factors yet to be defined to increase its efficacy, especially if it is intended to treat cancer patients. First and foremost, the off-target effect of CRIPSR system makes it difficult for the researchers to target a specific genomic locus. Elaborating, Daisy teaches that this is because CRISPR-based editing usually creates indels at undesired loci of the genome. Continuation of genetic modification at that point would obviously raise the risk of toxicity in adjacent normal cells and unwanted mutations. Hence, while designing CRISPR-based technology in oncology research, it is detrimental to identify and take control over the off-target events. Continuing, Daisy notes that besides the editing efficiency is yet another hurdle which has to be sorted out before implementing CRISPR-based therapeutics for oncological therapy. The efficiency of NHEJ and HDR in repair of double stranded DNA break is one among the important determining factors for overall gene editing efficiency. The efficacy of NHEJ and HDR in DNA repair varies for different cell types. Broadly speaking, NHEJ is an error-prone mechanism, which incorporates indels at the site of cleavage; HDR, on the other side, replaces the target gene with a recombinant alternative sequence. However, HDR template requires a viral or non-viral vector for translocation into the nucleus. Hence, strategies such as nanocarriers, to enhance the productivity of HDR template delivery into the nucleus along with co-delivery of CRISPR components would increase the specificity and efficiency of gene editing or gene correction in tumors. Though the off-target effect and efficient delivery is resolved, ‘how fit the edited cells are?’ is another unanswered question. If the CRISPR- edited cells possess great adaptability and proliferation rate than the unedited counterparts, then these edited ones can reach the therapeutic threshold essential for fruitful treatment upshots. However, Daisy cautions that if the editing efficiency is low, or the edited cells are not able to adapt themselves like the unedited ones, this pitfall will have a huge effect on the expected therapeutic outcome. Hence, Daisy adds that modification of the genome of the edited cells in vitro, followed by reinfusion of the cells back to the patients would help to overcome this obstacle at least partially. Last but not least, the immune response provoked by the Cas9 protein upon entry into patient’s body is another limiting factor. This is due to the presence of short peptides on the surface of Cas9 which acts as epitopes that can bind to the MHC molecules. In fact, previous literature has reported that the immunogenicity caused by CRISPR-Cas9 technique was the prime factor for destabilization of the host cell. Hence, strategies to minimize the host response following delivery of CRISPR-Cas system has to be framed before carrying this system to patient setting (paragraph bridging Pg. 101 and Pg. 102).
Unpacking the teachings of Daisy makes clear that even if one of ordinary skill in the art successfully designs crRNAs for the target sequence, the success of CRISPR in vivo is not a foregone conclusion. Daisy lists off-target effects, efficiency of NHEJ and HDR in repair of double stranded DNA break, and method of delivery of CRISPR components as a few of the known challenges facing CRISPR mediated cancer therapy. Further exacerbating CRISPR mediated cancer therapy is the possibility of an adverse reaction by the patient as a consequence of the introduction of exogenous material into said patient. The specification fails to address any of the known in vivo challenges espoused in Daisy.
The level of Predictability in the Art/Conclusion: In essence, the specification merely presents an idea of, and leaves it entirely up to the practitioner to determine whether the method would produce a therapeutically relevant effect (i.e. killing cancer cells), and if so, how to carry out the claimed method. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable the skilled artisan to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 USC 112, first paragraph.
Simply put, the specification provides no direction or guidance to killing cancer cells. There are no working examples- in vitro or in vivo- and the prophetic example is not drawn to claims that are under consideration. Plainly stated, the prophetic example of designing crRNAs does not enable a method of killing cancer cells with CRISPR. The prior art, as exemplified in this action, is replete with critical and unanswered questions regarding CRISPR mediated cancer therapy. The specification neither addresses nor provides solutions to these questions. As a consequence, one of ordinary skill in the art would not know how to use the invention as claimed, throughout its entire scope, without undue experimentation.
Applicant’s Arguments/Response to Arguments
Applicant argues: The only enablement issue directly addressed by the Examiner is based on the Examiner’s interpretation of the claim language as defining a method where all treated cancer cells must necessarily be killed. Such a requirement is not specified in the claims.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. The preamble of claim 1 is copied below.
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A plain reading of the preamble indicates an animal comprising two cell populations- cancer cells that comprise at least one DNA sequence and healthy cells that do not comprise the DNA sequence found in cancer cells.
Continuing, the end of the claim recites the following:
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A plain reading of this section of claim 1 indicates the cancer cells that comprise the at least one DNA sequence are killed. Therefore, it is unclear which cancer cells are not killed. Are there cancer cells in the animal that do not contain the DNA sequence? If so, Applicant should cite, specifically, where claim 1 recites such a feature. Moreover, note that the comparison of the cell populations- cancer cells that that comprise at least one DNA sequence and healthy cells that do not comprise the at least one DNA sequence. This is contrast to what Applicant suggests - cancer cells that that comprise at least one DNA sequence and cancer cells that do not comprise the at least one DNA sequence. Therefore, it is reasonable to conclude that all the cancer cells in the animal have the least one DNA sequence. And as such, the claim requires all cancer cells to be killed as a result of disruption of nucleic acid molecules that comprise the at least one DNA sequence.
Applicant argues: The art cited by the Examiner is not relevant.
In Response: Per MPEP 2164.03, the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. (Examiner’s emphasis). The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
The claimed invention is drawn to a method of killing cancer cells. The specification fails to teach exactly how to make the composition and then use the composition to kill cancer cells. Each of the references cited by the Examiner is drawn to cancer gene therapy or CRISPR. The 4/27/23 Møller declaration cites two publications- Jiang et al. and Kwon et al.- that were filed after the priority date of the instant application and that Declarant suggests reproduces the findings of the specification. Examiner previously noted that these references taught various procedures not contemplated in the as-filed specification. In fact, Kwon explicitly teaches their method was “non-explored”. Thus, it cannot be said that a “non-explored” method provides an enabling disclosure for a previously filed patent application.
The 10/9/2024 Møller declaration states that targeting as few as four cancer cell-specific genomic sequences had significant impact on the number of viable cells compared to the controls and that by increasing the number of targeted sequences to ten or twenty, significant reductions it tumor cell viability were document in all experiments. Said another way, only some cancer cells comprising a DNA sequence that was not present in healthy cells were killed. This is problematic because the claims are NOT drawn to a method of having significant impact on the number of viable cancer cells NOR are the claims drawn to a method of having significant reductions in tumor cell viability. Rather, the claims require all cancer cells that comprise a
DNA sequence that is not present in healthy cells be killed. To be of probative value, any secondary evidence- such as the 10/9/2024 37 CFR 1.132 Declaration filed by Applicant- must be related to the claimed invention (nexus required). See MPEP 716.01 (b).
Applicant argues: The fact that a drug might induce adverse events is not a
sufficient reason to state that the use of the drug is not enabled.
In Response: Examiner did not state that the fact that a drug might induce an adverse event was the reason for its use to not be enabled. Rather, and as previously stated above,” Further exacerbating CRISPR mediated cancer therapy is the possibility of an adverse reaction by the patient as a consequence of the introduction of exogenous material into said patient.”
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Prior Art Rejection 1
Claim(s) 1-2, 6, 16,19-20,23-25 and 28 remain rejected under 35 U.S.C. 102 (a) (1)/(a)(2) as being anticipated by Angel et al. (WO2014071219A1, Filed 11/1/2013, Published 5/8/2014). The rejection is copied below for Applicant’s convenience.
Angel discloses many cancer cells express survivin, a member of the inhibitor of apoptosis (LAP) protein family that, in humans, is encoded by the BIRC5 gene. Using RNA interference to reduce expression of certain mRNA molecules, including survivin mRNA, can transiently inhibit the growth of certain cancer cells. However, Angel explains that previous methods of using RNA interference to reduce expression of survivin mRNA yield temporary effects, and result in only a short increase in mean time-to-death (TTD) in animal models. Angel notes that it has now been discovered that inducing a cell to express one or more gene-editing proteins that target the BIRC5 gene can result in disruption of the BIRC5 gene, can induce the cell to express and/or secrete a non- functional variant of survivin protein, can induce the cell to express and/or secrete a dominant-negative variant of survivin protein, can trigger activation of one or more apoptosis pathways in the cell and nearby cells , can slow or halt the growth of the cell and nearby cells, can result in the death of the cell and nearby cells, can inhibit the progression of cancer, and can result in remission in a cancer patient (Pg. 33, para. 2).
Towards this end, and with regards to claim 1 (3), claim 20 (3) and claim 23 (3), Angel discloses a method for killing cancer cells in a human being (as in claim 24, claim 25 and claim 28) (Pg. 25, para. 1), the method comprising induction of preferential killing of cancer cells that comprise at least one DNA sequence, which is not present in or is not present in significant amounts in healthy cells of said human being (Pg. 28, last paragraph), by administering (Pg. 3, last paragraph) an effective amount of a nucleic acid (as in claim 6 and claim 23 (in-part)) that specifically recognizes at least one of said at least one DNA sequences and an effective amount of at least one molecule that selectively disrupts DNA comprising said at least one DNA sequence when bound to said recognition molecule (Pg. 22, para. 1). Angel discloses the gene-editing protein creates one or more nicks or double-strand breaks in the DNA of the cell (as in claim 16 and claim 23 (in-part)) (Pg. 34, line 5+), such that cancer cells are killed. Regarding claim 2, claim 20 (in-part) and claim 23 (in-part), Angel discloses the human being is not exposed to any recognition molecule that recognizes the animal’s autologous DNA in healthy cells (paragraph bridging Pg. 32 and 33). Continuing, Angel discloses the target cancer cell is modified by inserting the nucleic-acid sequence into a safe-harbor location (as in claim 19) (Pg. 28, para. 1). Absent a definition in the specification, note that the examiner has interpreted ‘a preventive or therapeutic depot’ as a safe harbor location.
Accordingly, Angel anticipates the claimed invention.
Applicant’s Arguments/Response to Arguments
Applicant argues: Angel fails to teach or suggest targeting genetic material that can only be found in cancer cells in a patient. On the contrary, Angel teaches that genes that are all present in normal healthy cells.
In Response: As noted in the paragraph cited above (Pg. 28, last paragraph), Angel teaches
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At claim 21, Angel claims a nucleic acid encoding a gene-editing protein, wherein the gene-editing protein targets a sequence that is not present in the non-cancer human genome.
At claim 22, Angel claims a nucleic acid encoding a gene-editing protein, wherein the gene-editing protein targets a member of: a viral sequence, a bacterial sequence, a fungal sequence, a parasite sequence, and a cancer-genome sequence. When taken in context with the paragraph cited above, it is clear that Angel does not teach genes that are all present in normal healthy cells, as alleged by Applicant.
Applicant argues: If one targets a cancer specific gene consisting of 600 nucleotides, this does not ensure that normal cells are not targeted because the 600 nucleotides include multiple potential shorter recognition sequence targets, which are not specific for the cancer-specific gene. Therefore, a purposive selection of he target DNA sequence(s) has to be made to ensure that the recognition molecule is indeed specific in its targeting of the cancer-specific sequence. This selection is not disclosed or hinted at in Angel.
In Response: At claim 21, Angel claims a nucleic acid encoding a gene-editing protein, wherein the gene-editing protein targets a sequence that is not present in the non-cancer human genome. At claim 22, Angel claims a nucleic acid encoding a gene-editing protein, wherein the gene-editing protein targets a member of: a viral sequence, a bacterial sequence, a fungal sequence, a parasite sequence, and a cancer-genome sequence.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 7-8, 21-22, 26 and 29-33 remain rejected under 35 U.S.C. 103 as being unpatentable over Angel et al. (WO2014071219A1, Filed 11/1/2013, Published 5/8/2014, FOR Patent Ref. 1 in IDS filed 5/11/2018) as applied to claims 1-2, 6, 16,19-20,23-25 and 28 and further in view of Prasad et al. (PgPub US20190112358A1, Filed 11/13/2015) and Zhang et al. (PgPub US20140179770A1, Published 6/26/2014).
As noted above, and with regards to claim 21 and claim 22, Angel teaches a method for killing cancer cells in a human being (as in claim 26 and claim 27 ) (Pg. 25, para. 1), the method comprising induction of preferential killing of cancer cells that comprise at least one DNA sequence, which is not present in or is not present in significant amounts in healthy cells of said human being (Pg. 28, last paragraph), by administering (Pg. 3, last paragraph) an effective amount of a nucleic acid that specifically recognizes at least one of said at least one DNA sequences and an effective amount of at least one molecule that selectively disrupts DNA comprising said at least one DNA sequence when bound to said recognition molecule (Pg. 22, para. 1). Note that Angel further teaches the ‘at least one molecule that selectively disrupts DNA’ is a nucleic acid and that both nucleic acids are comprised in at least one expression vector (as in claim 21 (1,2) and claim 22 (1,2)) (Pg. 21, para. 1; Pg. 12, para. 1).Moreover, Angel teaches the human being is not exposed to any recognition molecule that recognizes the animal’s autologous DNA in healthy cells (as further in claim 22) (paragraph bridging Pg. 32 and 33).
However, Angel fails to teach the recognition molecule is a crRNA and the molecule that selectively disrupts DNA is a Cas protein (as in claim 7, as in claim 21 (in-part) and claim 22 (in-part).
Before the effective filing date of the claimed invention, Prasad et al. taught methods of using CRISPR-Cas systems to modify the genome of a cell (Pg. 5,para. 101). Prasad teaches wo components must be introduced and/or expressed in cells or an organism to perform CRISPR based genome editing: the Cas9 nuclease and a ‘guide RNA’ (gRNA),wherein said gRNA comprises a crRNA (as in claim 7, claim 8, claim 21 (in-part) and claim 22 (in-part)) (Pg. 19, para. 363; Pg. 4-5, para. 94-99). Prassad explains that a crucial step in targeted genome editing at genomic loci that need to be modified, is the introduction of double stranded breaks (DSBs). Once, DSBs are introduced, they are repaired either by non-homologous end joining (NHEJ) or homology directed repair (HDR). NHEJ is known for the efficient introduction of insertion/deletion mutations (indels) that in turn cause disruption of the translational reading frame of the target coding sequence or at binding sites of trans-acting factors in promoters or enhancers (Pg. 11,para. 269-269). Prassad teaches a primary target is to create mutations at the target site. Prassad teaches insertion and deletions (indels) through CRISPR/Cas at this location makes the targeted gene non-functional. In addition, frame shift mutations also cause premature translation stop codons, therefore leading to a non-functional target gene and an absence of downstream sequences (as in claim 17, claim 18 and further claim 23) (Pg. 12, para. 305).
However, none of Angel et al. nor Prassad et al. teach a step of in vitro testing prior to administration of composition to the animal (as further in claims 29-33).
Before the effective filing date of the claimed invention, Zhang et al. taught performing an in vitro validation test on CRISPR-Cas9 constructs in 293 cells and human ES cells prior to use in an in vivo model (as in claim 29, 30, claim 31, claim 32 and claim 33) (Pg. 97,para. 813-816).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Angel et al., wherein Angel teaches a CRISPR-Cas mediated method for killing cancer cells in a human being, the method comprising induction of preferential killing of cancer cells that comprise at least one target DNA sequence that is not present in or is not present in significant amounts in healthy cells of said human being, with the teachings of Prasad et al., wherein Prassad teaches using a CRISPR-Cas system to modify the genome of a cell using a Cas9 nuclease and a crRNA comprising guide RNA, wherein the modification introduces indels into the targeted DNA sequence such that the targeted DNA sequence is rendered non-functional, with a reasonable expectation of arriving at the claimed invention. That is, for the objective of preferential killing of cancer cells that comprise at least one target DNA sequence that is not present in or is not present in significant amounts in healthy cells of said human being, one of ordinary skill in the art would have used the method of Prassad to render the at least one target DNA sequence in the cancer cell of Angel non-functional.
Moreover, one of ordinary skill in the art would have found it prima facie obvious to perform an in vitro validation test of the CRISPR-Cas system of Angel in view of Prassad in order to test the efficacy and safety of the system in an in vitro setting prior to its in vivo application.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Applicant’s Arguments/Response to Arguments
Applicant argues: None of Angel, Prasad or Zhang, individually or in combination, fail to render Applicant’s method obvious.
In Response: Arguments drawn to Angel have been addressed above. Prasad and Zhang are cited for the reasons above.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 extension fee 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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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632