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
Applicant’s election without traverse of Group I (claims 1-16, 27, 29-37, 39, 43, 45-47, 50-53, 55-57, 63-66, 69, 71, 74, 75, and 77) drawn to a method for analyzing for or detecting the presence of enhancers of adeno- associated virus (AAV) vector cell transduction in a biological sample from a subject) in the reply filed on September 11, 2024, is acknowledged.
Applicant further elected Method Species A, corresponding to claims 1 and 69.
Claims 2-16, 27, 29-37, 39, 43, 45-47, 50-53, 55-57, 63-66, 75, and 77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II and Species B-E), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 11, 2024.
DETAILED ACTION
The amended claims filed on July 17, 2025, have been acknowledged. Claims 17-26, 28, 38, 40-42, 44, 48-49, 54, 58-62, 67-68, 70-74, 76, and 78-85 were cancelled. Claims 86-88 are new. In light of the Applicant’s elected group and species, claims 2-16, 27, 29-37, 39, 43, 45-47, 50-53, 55-57, 63-66, 75, and 77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 69, and 86-88 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/768,665, filed on November 16, 2018. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 69. And 86-88 receive domestic benefit from U.S. provisional application No. 62/768,665, filed on November 16, 2018.
Maintained Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 69 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. This rejection is repeated with regards to the rejection in the Non-final Office action mailed on September 5, 2025. Applicant’s traversal is addressed below.
Claim 1 is directed to a method for analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they are not substantially more.
The claims are drawn to a method for analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject. Thus the claims are drawn to a method and thus generally drawn to a process.
With Respect to Step 2A, prong one, the judicial exception, the claim is directed to a method step of “analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject”. The step of analyzing or detecting is an abstract idea or mental thought performed by the artisan, and thus directed to a judicial exception (Step 2A, prong one: Yes)
With respect to Step 2A. prong two, in University of Utah Research v. Ambry Genetics the courts stated, “Recently in Alice the Supreme Court reiterated its two-step test to determine patent eligibility for any claims that allegedly encompass abstract ideas. First, “we determine whether the claims at issue are directed to [a] patent-ineligible concept[]. If so, we then ask, ‘what else is there in the claims before us?’” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1296–97) (citations and punctuation omitted). That is, we next ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “‘transform the nature of the claim’ into a patent-eligible application.” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297). Put another way, there must be a further “inventive concept” to take the claim into the realm of patent eligibility.”
In the instant case, the claim provides two measuring steps in subclaim steps (d), and (j) to determine MAX and S.EV, respectively and a comparing step of comparing S.EV to MAX to determine if there are enhancers in the biological sample of the subject. These steps are generic as they provide no specific reagents, conditions, or guidance such that these additional steps fail to provide a further inventive concept. Thus these additional steps are considered conventional data gathering steps.
Thus the claims do not recite any elements or steps that add anything significant to the judicial exception. The recited steps must be undertaken to apply the judicial exceptions. The recited steps only instruct the user to engage in well-understood, routine and conventional activity previously engaged in by scientists in the field since methods of analyzing transgenic protein expression were conventional in the art at the time the invention was made. See Ariosa Diagnostics, Inc. v. Sequenom, Inc., F. Supp. 2d, 2013 WL 5863022, at *10 (N.D. Cal. Oct. 30, 2013) noting that "had the inventors of the [patent-in-suit] created an innovative method of performing DNA detection while searching for paternally inherited cffDNA, such as a new method of amplification or fractionation, those claims would be patentable.” (Step 2A: No).
Further, the claims do not recite any elements or steps that do more than describe the judicial exceptions with instructions for applying it. See, for example, Prometheus, 132 S. Ct. at 1297. For example, although the claim recites the contingent limitations that if said S.EV is greater than said MAX the biological sample from said subject contains enhancers of AAV vector cell transduction, this is a mere correlation that is the consequence of how a transgene and resulting protein are regulated by the cell.
The claims also do not require the use of a particular machine, wherein the particular machine implements one or more of the judicial exceptions or integrates the judicial exception(s) into a particular practical application.
Note that the Supreme Court in Mayo v. Prometheus made clear that to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply state the law of nature while adding the words "apply it." Essentially, appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patent-eligible.
In Mayo v. Prometheus, the Court found that "[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Additionally, "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law". Flook, 437 U. S., at 590; see also Bilski, 561 U.S., at __ (slip op., at 14) ("[T]he prohibition against patenting abstract ideas 'cannot be circumvented by'.., adding 'insignificant post-solution activity'" (quoting Diehr, supra, at 191-192)).
The Court summarized their holding by stating "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
Applicant’s attention is also directed to PerkinElmer, Inc. v. Intema Ltd., 496 F. App'x 65 (Fed. Cir.16 2012) and the recent Report and Recommendation in Genetic Tech v. LabCorp and 23AndMe (D. Del. September 2014) available via url: < ded.uscourts.gov/sites/default/files/opinions/cjb/2014/september/12-1736.pdf> and MYRIAD GENETICS, INC., v. AMBRY GENETICS CORPORATION, CAFC, 2014.
With respect to Step 2B, the claim is not considered to recite additional elements that amount to significantly more than the judicial exception itself, as described above (Step 2B: No).
For the reasons set forth above, the claims are not considered to recite something significantly different than a judicial exception and thereby are not directed to patent eligible subject matter.
Response to Arguments
Applicant's arguments filed March 5, 2026, are acknowledged.
Applicant argues that the instantly claimed method is not well-understood, routine, or conventional in the field. Applicant argues that their method provides the potential for technical improvements in the field of assays for detecting enhancers of AAV vector cell transduction, such as increased speed to complete the assay. As such, the instantly claimed methods of claims 1 and 69 are not directed to a judicial exception without significantly more (page 2, paragraph 3-page 3, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
Furthermore, MPEP 2145(I) states that an argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration. As such, although Applicant asserts that their method provides technical improvements for detecting enhancers of AAV cell transduction, they have not provided any evidence that this is the case. The statements cited in the specification by the Applicant are also mere assertions of perceived advantages of the method and not evidence of a technical improvement.
Furthermore, as identified by the cited art used in the 103 rejection below, the steps used in the instantly claimed methods were obvious and would have been considered routine and conventional in the field.
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.
Claims 1, 69, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Gene Therapy 24: 49-59. 2017) and World Intellectual Property Organization Patent Application No. 2013/078400 (Mingozzi). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on September 5, 2025. Applicant’s traversal is addressed below.
Wang teaches a method for analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject, comprising:
(a) providing infectious recombinant AAV particles comprising a recombinant AAV vector, wherein (Particles of AAV/luc vector (1 × 108) were incubated with PBS for 2 h at 4 °C. The mixture of AAV vector and PBS was used to transduce 1 × 105 Huh7 cells in a 48-well plate in the presence of adenovirus dl309 at MOI of 5 (Figure 1))
(i) said vector comprises a reporter transgene (the AAV/luc vector comprises a luciferase reporter gene (Figure 1)),
(ii) said reporter transgene comprises a single-stranded (AAV vectors comprise single stranded DNA),
(iii) said reporter transgene is operably linked to one or more expression regulatory element (Wang teaches that the AAV transgene plasmid is pTR/CBA-luc. The CBA corresponds to the chicken beta actin promoter (a regulatory element) (page 56, column 2, paragraph 4); and
(iv) said reporter transgene is flanked by one or more flanking element (AAV vectors comprise ITRs that flank the transgene);
(b) providing cells that can be infected with said infectious recombinant AAV particles (The mixture of AAV vector and PBS was used to transduce 1 × 105 Huh7 cells in a 48-well plate in the presence of adenovirus dl309 at MOI of 5 (Figure 1));
(c) contacting said cells of (b) with said infectious recombinant AAV particles of (a) under conditions in which said cells of (b) are transduced by said infectious recombinant AAV particles of (a) and said reporter transgene is expressed by said cells of (b) (The mixture of AAV vector and PBS was used to transduce 1 × 105 Huh7 cells in a 48-well plate in the presence of adenovirus dl309 at MOI of 5 (Figure 1));
(d) measuring expression of said reporter transgene and assigning a value denoted MAX that reflects the amount of reporter transgene expression of (c) (After 24 h, luciferase activity from the cell lysate was analyzed. The fold increase of transgene expression from sera incubation was calculated by comparison with PBS (Figure 1));
(e) providing infectious recombinant AAV particles of (a) (Particles of AAV/luc vector (1 × 108) were incubated with 1:500 diluted human sera for 2 h at 4 °C. The mixture of AAV vector and sera was used to transduce 1 × 105 Huh7 cells in a 48-well plate in the presence of adenovirus dl309 at MOI of 5 (Figure 1);
(f) providing a biological sample from a subject (Particles of AAV/luc vector (1 × 108) were incubated with 1:500 diluted human sera for 2 h at 4 °C. The mixture of AAV vector and sera was used to transduce 1 × 105 Huh7 cells in a 48-well plate in the presence of adenovirus dl309 at MOI of 5 (Figure 1);
(g) providing cells that can be infected with said infectious recombinant AAV particles (Particles of AAV/luc vector (1 × 108) were incubated with 1:500 diluted human sera for 2 h at 4 °C. The mixture of AAV vector and sera was used to transduce 1 × 105 Huh7 cells in a 48-well plate in the presence of adenovirus dl309 at MOI of 5 (Figure 1);
(j) measuring expression of said reporter transgene and assigning a value denoted S.EV that reflects the amount of reporter transgene expression of (i) (After 24 h, luciferase activity from the cell lysate was analyzed. The fold increase of transgene expression from sera incubation was calculated by comparison with PBS (Figure 1));
(k) comparing said S.EV to said MAX, wherein if said S.EV is greater than said MAX the biological sample from said subject contains enhancers of AAV vector cell transduction (After 24 h, luciferase activity from the cell lysate was analyzed. The fold increase of transgene expression from sera incubation was calculated by comparison with PBS (Figure 1)).
Wang discloses that in their study, they have identified several proteins from human serum, which directly interact with AAV virions and have the potential to impact AAV transduction (page 50, column 1, paragraph 1 and Figure S1).
Wang does not teach wherein the biological sample of (f) is mixed with empty capsid AAV particles to produce a mixture (M) and incubating said M under conditions allowing said empty capsid AAV particles to bind to any AAV binding antibodies present in said biological sample nor (i) contacting said cells of (g) with said M and said infectious recombinant AAV particles of (e) under conditions in which said infectious recombinant AAV particles of (e) can transduce said cells of (g) and express said reporter transgene in said cells of (g).
However, Mingozzi teaches a method of measuring anti-AAV antibody-mediated neutralization in vitro wherein a reporter AAV8 vector expressing luciferase was incubated with increasing dilutions of pooled normal plasma alone (0X) or in the presence of increasing amounts of AAV585/8 empty capsids (10X, 100X, 1000X the amount of AAV8-Luciferase vector). After one hour incubation at 37°C, vectors were used to transduce HEK293 cells in vitro. Percent inhibition was measured relative to a control in which the reporter vector was incubated with medium only instead of pooled plasma. The addition of increasing amounts of AAV585/8 empty capsids protects the AAV8-Luciferase vector from antibody-mediated neutralization (paragraph 0024 and Figure 7).
Mingozzi teaches that adult human sera has neutralizing antibodies (Nabs) that cause a significant reduction in viral transduction of a target cell. To evaluate individuals more rigorously, a series of sera from hemophilia subjects were screened using an in vitro NAb assay. Among those samples with a low NAb titer (from 1 to 3), a broad range of neutralizing activity in undiluted serum was measured (Table 1). Despite the pre-selection of subjects with low NAb titer, the dot blot analysis showed a marked variation in the amounts of total anti-AA V antibodies (both neutralizing and nonneutralizing) detected. These results indicate that adult human subjects who appear to have low-titer neutralizing antibodies (NAb) to AAV carry significant amounts of anti-AAV IgG not reliably detected by routine assays for NAb. (paragraphs 0006 and 125-127).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method for analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject of Wang with the method step of protecting AAV vectors from antibody-mediated neutralization by including empty AAV vector as taught by Mingozzi to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Mingozzi teaches that adult human sera is known to have neutralizing antibodies that cause a significant reduction in viral transduction of a target cell. By mixing empty capsids and the human sera, the AAV/Luc vector can be protected from neutralization. Furthermore, as human sera has a wide variation in the levels of neutralizing antibodies, it would also be obvious to use the empty capsids the protect the AAV vectors from neutralization in order to reduce the variability in the data between experiments, allowing for a more accurate assessment of the enhancer qualities of the sera/compounds within the specific type of sera and specific type of AAV vectors used in the method of Wang. In other words, Wang teaches that there are multiple possible enhancers in human serum (e.g. Table S1) that were to be analyzed, as well as other isotypes of AAV that would need to be analyzed in the presence of empty AAV vectors in order to protect from neutralizing antibodies. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 69, Wang teaches that luciferase activity was measured with a Wallac1420 Victor 2 (Marshall Scientific, Hampton, NH, USA) automated plate reader (page 56, column 2, paragraph 6). As such, Wang teaches that steps d and j are automated.
Regarding claim 88, Wang teaches that to study the phenotypic correction using AAV vectors incubated with HSA, they used hemophilia B mice as a disease model and
AAV8/FIX-OPT, which has been used in Phase I clinical trials in patients with hemophilia B. over fivefold higher FIX levels were detected in mice incubated with AAV8/FIX-OPT than those with the same vectors treated with PBS. Similarly, plasma FIX activity was much higher in mice receiving vector treated with HSA (page 53, column 2, paragraph 2-page 54, column 1, paragraph 1).
Wang does not teach wherein if S.EV is greater than MAX, said subject is treated with AAV based gene therapy.
However, Mingozzi teaches that despite the promise of AAV based gene therapy approaches for treatment of a variety of disorders, immune responses occur following exposure to adeno-associated virus (AAV) or AAV vectors, and these protective responses may limit therapeutic efficacy of AAV vectors. Humoral responses (anti-AAV neutralizing antibodies, or NAb) often give rise to viral neutralization causing a significant reduction in viral transduction of the target cell, thereby limiting the amount of therapeutic polypeptide delivered. Anti-AAV neutralizing antibodies can efficiently neutralize AAV vectors; this has been reported in humans. An additional complication is that the assays currently in place to screen for NAb are not very sensitive, and therefore even subjects who test negative or low titer on these assays may in fact have low levels of anti-AAV antibodies sufficient to block AAV transduction. Mingozzi teaches a formulation comprising a predetermined ratio of viral vectors and empty capsids, wherein the viral vector includes a transgene and the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation in said patient (paragraphs 0006-0009).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method for analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject of Wang with the method step of predetermining the ratio of viral vectors and empty capsids, wherein the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation after administration to said patient and administering the vector to the patient as taught by Mingozzi to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Mingozzi teaches that despite the promise of AAV based gene therapy approaches for treatment of a variety of disorders, immune responses occur following exposure to adeno-associated virus (AAV) or AAV vectors, and these protective responses may limit therapeutic efficacy of AAV vectors. Anti-AAV neutralizing antibodies can efficiently neutralize AAV vectors; this has been reported in humans. An additional complication is that the assays currently in place to screen for NAb are not very sensitive, and therefore even subjects who test negative or low titer on these assays may in fact have low levels of anti-AAV antibodies sufficient to block AAV transduction. Mingozzi teaches a formulation comprising a predetermined ratio of viral vectors and empty capsids, wherein the viral vector includes a transgene and the predetermined amount of empty capsids is calculated to inhibit undesired immune responses to said formulation in said patient. As Mingozzi teaches that the assays currently in place to screen for NAb are not very sensitive, and therefore even subjects who test negative or low titer on these assays may in fact have low levels of anti-AAV antibodies sufficient to block AAV transduction, it would have been obvious to determine the amount of empty capsids required to inhibit undesired immune responses to said formulation in said patient before administering the vectors to a patient with transduction enhancers in their biological sample as this will also lead to improved viral transduction in the patient. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed March 5, 2026, are acknowledged.
Applicant argues that Wang and Mingozzi fail to disclose or suggest steps (e)-(i) of the claimed method, as it is the precise timing and combination of components which leads to the ability to determine if the biological sample from the subject contains enhancers of AAV vector cell transduction. More specifically, the claimed method calls for the production of a mixture produced by mixing the biological sample from the subject with the empty capsid AAV particles. This mixture is then subsequently contacted with cells at the same time the cells are contacted with the recombinant AAV particles. This differs from the Wang and Mingozzi.
Wang provides a method in which the AAV particle is first incubated with the biological sample, i.e., the HSA, for 2 hours, and then the biological sample and AAV particle is incubated with the IVIG, i.e., the AAV binding antibodies, for an additional 2 hours prior to exposing the AAV particle to the cells for transduction.
Thus, the instantly claimed method and Wang differ in that Wang allows for incubation of the neutralizing antibodies with the AAV vector prior to contacting the cells, whereas, the instantly claimed method requires contacting the cells with the AAV vector and the biological sample comprising the neutralizing antibodies at the same time. There is no preincubation step as disclosed by Wang.
Mingozzi fails to cure the deficiencies of Wang, as the methods disclosed in Mingozzi call for the production of a formulation of AAV vectors with the empty capsids, which are then used to transduce a cell or infect an animal model system, see, e.g., paragraphs [0128]- [0130] of Mingozzi. These paragraphs indicate that the AAV vectors are formulated in ten-fold (10X) excess of AAV empty capsids (see, e.g., [0129]) or nine-fold (9X) empty capsids (see, e.g., [0130]). Thus, the methods of Mingozzi fail to allow for mixing of the biological sample (f) with empty capsid AAV particles to produce a mixture (M) and incubating M under conditions allowing said empty capsid AAV particles to bind to any AAV binding antibodies present in said biological sample prior to contacting the cells with the mixture (M) and the recombinant AAV particles. Given that Wang does not disclose step (h), as indicated by the Examiner, both Wang and Mingozzi, alone and combined, fail to disclose each and every step of the instantly claimed methods (page 3, paragraph 3-page 6, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., contacting the cells with the AAV vector and the biological sample comprising the neutralizing antibodies at the same time without a preincubation step of the AAV vector with the biological sample) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997) (The court held that the PTO is not required, in the course of prosecution, to interpret claims in applications in the same manner as a court would interpret claims in an infringement suit. Rather, the “PTO applies to verbiage of the proposed claims the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in applicant’s specification.”). See MPEP 2111]
It is worth noting that the present claims do not require that there is no preincubation between the AAV vector and the sample. All that is required in claim 1 is contacting said cells of (g) with said M and said infectious recombinant AAV particles of (e) under conditions in which said infectious recombinant AAV particles of (e) can transduce said cells of (g) and express said reporter transgene in said cells of (g). Based on the claim language, the broadest reasonable interpretation encompasses scenarios in which there is preincubation of the AAV vector and the mixture M as long as the particles can still transduce and express the transgene.
Regarding Applicant’s arguments against Mingozzi, it is worth noting that Applicant’s cited passages of Mingozzi are focused on the effect of empty capsids on the efficiency of transduction of AAV vectors in vivo whereas the cited passages of Mingozzi in the rejection above is focused on assessing the effect of empty capsids on the efficiency of transduction of AAV vectors in vitro in HEK293 cells. As cited in rejection above, Mingozzi teaches a method of measuring anti-AAV antibody-mediated neutralization in vitro wherein a reporter AAV8 vector expressing luciferase was incubated with increasing dilutions of pooled normal plasma alone (0X) or in the presence of increasing amounts of AAV585/8 empty capsids (10X, 100X, 1000X the amount of AAV8-Luciferase vector). After one hour incubation at 37°C, vectors were used to transduce HEK293 cells in vitro. Percent inhibition was measured relative to a control in which the reporter vector was incubated with medium only instead of pooled plasma. The addition of increasing amounts of AAV585/8 empty capsids protects the AAV8-Luciferase vector from antibody-mediated neutralization (paragraph 0024 and Figure 7). Therefore, Mingozzi clearly teaches mixing of the biological sample (pooled normal plasma) with empty capsid AAV particles (AAV585/8) to produce a mixture (M) and incubating M under conditions allowing said empty capsid AAV particles to bind to any AAV binding antibodies present in said biological sample.
Therefore, Applicant’s arguments are considered unpersuasive.
Second, Applicant argues that Wang does not teach steps (h) and (i) and can therefore not teach steps (j) and (k) because they require step (i) and Mingozzi fails to make up for this deficiency (page 6, paragraphs 2-3).
Applicant's arguments have been fully considered but they are not persuasive.
in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Although Wang does not teach the steps of (h) and (i), Mingozzi does teach these steps. As stated supra, it would have been obvious to combine Wang and Mingozzi to remove the confounding variable of neutralizing antibodies and more accurately assess whether HSA or other serum proteins have an enhancing effect on AAV transduction. The combined method of Wang which teaches steps (a-g) and (j-k) and Mingozzi which teaches steps (h-i) would have all of the steps of the method of claim 1.
Claims 1, 69, and 86-87 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Gene Therapy 24: 49-59. 2017) and World Intellectual Property Organization Patent Application No. 2013/078400 (Mingozzi) as applied to claims 1 and 69 above, and in further view of Bradley et al. (Journal of Biomolecular Screening 9: 514-524. 2004), as evidenced by LabExchange (Tecan SpectraFluor Plus). This rejection is repeated with regards to the rejection in the Non-final Office action mailed on September 5, 2025. Applicant’s traversal was addressed above.
The teachings of Wang and Mingozzi are as discussed above.
The combined teachings of Wang and Mingozzi do not teach using an automated system as claimed in claim 86.
However, Bradley teaches an automated system for in vitro determination of inhibitors of HIV entry into cells. The automated system comprises:
Contacting components: Bradley teaches that their automated system dispenses CHO-Tat10 cells and HeLa-P4 cells (transfected with HIV-1 LTR) separately using 2 Multidrops for contactingat a 1:1 ratio and fusion to generate a fluorescent signal from the LacZ transgene
Measuring components: Bradley teaches that they added β-galactosidase quantification substrate using a Robolab Reagent addition stations and plates were read on a Tecan Spectrafluor Plus. Although Bradley does not specifically identify that the Tecan Spectrafluor Plus is connected to a computer for storing the data, LabExachange (page 2) evidences that the Tecan Spectrafluor Plus is a computer controlled fluorometer for measuring samples in a microplate and would store the fluorescent signal in a non-transitory electronic storage.
Mixing and incubating components: Bradley teaches that test compounds were transferred to the assay plates with a CyBiWell with a 384-tip head and control samples for max, min, and standard were added using Tecan Genesis to mix compounds with cells and then plates were incubated at 37°C in a Heraeus Cytomat.
Comparing components: Bradley teaches that to determine the effects of test compounds in the fusion assay, data were normalized to the controls on a per plate basis, and percentage activity values were calculated. Compounds tested at 10μM were considered “active” when they demonstrated > 30% inhibition compared to controls. For IC50 determinations, data were normalized to controls on a per plate basis and the percentage activity at each dose was calculated. Both sets of analyses were carried out using a software package (i.e. using the computer processor) (page 517, column 1, paragraph 2-page 522, column 2, paragraph 1 and Figures 1-8).
Bradley teaches that their fully automated system was employed in a high-throughput screen of ~ 650,000 compounds and a throughput of 40,000 data points per day was achieved which is considerably higher than that achievable with the previously described methods while maintaining high quality data (page 523, column 1, paragraph 3-column 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for analyzing for or detecting the presence of enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject of Wang and Mingozzi by using an automated system similar to Bradley to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Bradley teaches that their automated system allowed them to greatly increase the number of compounds tested which would also be useful in testing a multitude of biological samples from patients in an automated rather than manual method. Furthermore, although the method of using the automated system of Bradley is different than the method used by Wang and Mingozzi, the automated system of Bradley has all of the components necessary as recited by claim 86 and they can be modified to provide the specific components in the method of Wang and Mingozzi. For example, the 2 multidrops can be used to provide the cells for transduction and a solution comprising the AAV vectors, allowing for the concentration of cells or vectors to be adjusted to the ideal ratio. Furthermore, the CyBiWell can be used to deliver the biological sample to the plate while the Tecan Genesis can be used to deliver the empty AAV capsids. Additionally, the software for comparing the control and test compounds could be modified to use the MAX signal as a control and the S.EV signal as the test compound signal. Therefore, it would have been obvious that the method of Wang and Mingozzi could be modified to automate the process as shown by Bradley. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 87, as stated supra, Bradley teaches that the compounds tested at 10 μM were considered “active” when they demonstrated > 30% inhibition compared to controls (page 518, column 1, paragraph 2). As this would be an indication (i.e. > 30% inhibition) of suitability, it would have been obvious that a similar calculation could have been made based on the MAX and S.EV signals to give a readout that provides an indication of enhancers.
Conclusion
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 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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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631