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 .
DETAILED ACTION
The amendment filed August 18, 2026 in response to the Office Action of March 18, 2026 is acknowledged and has been entered.
Claims 84, 86, 87, 99-106, and 119-123 have been amended.
Claims 85, 88-90, and 108-110 have been cancelled.
Claims 1, 21, 41, 62, 84, 86, 87, 91-107, and 111-123 are pending.
Claims 1, 21, 41, 62, 102, and 122 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 84, 86, 87, 91-101, 103-107, 111-121, and 123 are currently under consideration as drawn to the elected invention.
In view of cancellation of claims 88-90 and 108-110 and claim 87 amendments, the 112(b) rejection set forth in the previous Office Action of March 18, 2026 is hereby cancelled.
Claims and 104 have been amended to recite limitations of previous claims 88-90 and 108-110 respectively. In view of the amendments, the 103 rejection set forth in the previous Office Action of March 18, 2026 is hereby cancelled.
Claims 84 and 104 have been amended to recite limitations of previous claims 88-90 and 108-110 respectively. In view of the amendments, the Double Patenting rejections set forth in the previous Office Action of March 18, 2026 are hereby cancelled.
In view of claim amendment, the 112(a) written description rejection set forth in the previous Office Action of March 18, 2026 is replaced by a 112(a) Enablement rejection.
Information Disclosure Statement
The Information Disclosure Statement filed on 08/06/2026 has been considered and entered by examiner.
NEW GROUNDS OF REJECTIONS
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 84, 86, 87, 91-101, 103-107, 111-121, and 123 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.
Claim 84 recites the limitation "the functions of akl" in line 12 on page 5. There is insufficient antecedent basis for this limitation in the claim.
Claim 84 recites the limitation "the correlation of the response score with…" in line 12 on page 5. There is insufficient antecedent basis for “the correlation” or “the response score” in the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 84 recites the broad recitation "the functions of akl": wherein the functions
a
k
l
depends on a distance
r
j
-
r
i
of each cell j to each cell i , and the claim also recites "the functions of akl": wherein the functions
a
k
l
depends on the distance
r
j
-
r
i
of the cell j to the cell i in the relation:
a
k
l
r
j
-
r
i
=
A
k
l
* exp(-
r
j
-
r
i
/
r
n
o
r
m
) with predefined constant coefficients
A
00
,
A
11
,
A
20
,
A
02
; and wherein the coefficients
A
00
,
A
11
,
A
20
,
A
02
, d and
r
n
o
r
m
are determined by optimizing the correlation of the response score with a therapy response of a cohort of training patients, which is the narrower statement of the recitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 104 recites the limitation "the functions of akl" in line 12 on page 9. There is insufficient antecedent basis for this limitation in the claim.
Claim 104 recites the limitation "the correlation of the response score with…" in line 12 on page 5. There is insufficient antecedent basis for “the correlation” in the claim.
Similar to claim 84, claim 104 also defines “the functions akl” in two different ways, i.e. a broad definition and narrow definition. Thus, as set forth above, the claim is indefinite.
Claims 86, 87, 91-101, 103, 105-107, 111-121, and 123 are also rejected because these claims depend on the rejected claims directly or indirectly.
Claim Rejections - 35 USC § 112(a)
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 84, 86, 87, 91-101, 103-107, 111-121, and 123 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claims 84 and 104 were amended after the filing date. The limitation of “wherein
O
D
M
j
is an optical density of the dye signal in the membrane of cell j, and wherein
O
D
C
j
is an optical density of the dye signal in the cytoplasm of cell j” in claims 84 and 104 has no clear support in the specification as originally filed. Applicants argue that support for new claims can be found at least in the original claims 88-90, 108-110, and Fig. 26. However, the original claims and figure only disclose: “wherein
O
D
M
j
is an optical density of the brown DAB signal in the membrane of cell j, and wherein
O
D
C
j
is an optical density of the brown DAB signal in the cytoplasm of cell j”.
Thus, the subject matter claimed in claims 84 and 104 broadens the scope of the invention as originally disclosed in the specification and claims from what was originally disclosed in the specification and claims as filed. Dependent claims also encompass the new matter, thus, dependent claims are also rejected.
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 84, 86, 87, 91-101, 103-107, 111-121, and 123 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. 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. This is a ENABLEMENT rejection
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The instant claims are drawn to a method of treating cancer comprising ……; computing for each cancer cell a single-cell ADC score based on the staining intensities of the dye in the cancer cell’s membrane; generating a treatment score by aggregating all single-cell ADC scores of the tissue sample using a statistical operation; …… and wherein the single-cell ADC score for a cell i is calculated as:
a sum of all cells j with
r
j
-
r
i
<
d
{
a
20
r
j
-
r
i
*
O
D
M
j
2
+
a
11
r
j
-
r
i
*
O
D
M
j
*
O
D
C
j
;
+
a
02
(
r
j
-
r
i
)
O
D
C
j
2
+
a
00
(
r
j
-
r
i
)
}
,
wherein the functions
a
k
l
depends on a distance
r
j
-
r
i
of each cell j to each cell i, wherein
O
D
M
j
is an optical density of the dye signal in the membrane of cell j, and wherein
O
D
C
j
is an optical density of the dye signal in the cytoplasm of cell j;
wherein the functions
a
k
l
depends on the distance
r
j
-
r
i
of the cell j to the cell i in the relation:
a
k
l
r
j
-
r
i
=
A
k
l
* exp(-
r
j
-
r
i
/
r
n
o
r
m
) with predefined constant coefficients
A
00
,
A
11
,
A
20
,
A
02
; and wherein the coefficients
A
00
,
A
11
,
A
20
,
A
02
, d and
r
n
o
r
m
are determined by optimizing the correlation of the response score with a therapy response of a cohort of training patients (claim 84),
or a method of treating cancer ……, the method comprising: administering the ADC to the cancer patient if a response score exceeds a predetermined threshold, wherein the response score was generated by aggregating single-cell ADC scores of a tissue sample of the cancer patient using a statistical operation, wherein each single-cell ADC score was computed for each cancer cell based on staining intensity of a dye in the membrane, …… and wherein the single-cell ADC score for a cell i is calculated as:
a sum of all cells j with
r
j
-
r
i
<
d
{
a
20
r
j
-
r
i
*
O
D
M
j
2
+
a
11
r
j
-
r
i
*
O
D
M
j
*
O
D
C
j
;
+
a
02
(
r
j
-
r
i
)
O
D
C
j
2
+
a
00
(
r
j
-
r
i
)
}
,
wherein the functions
a
k
l
depends on a distance
r
j
-
r
i
of each cell j to each cell i, wherein
O
D
M
j
is an optical density of the dye signal in the membrane of cell j, and wherein
O
D
C
j
is an optical density of the dye signal in the cytoplasm of cell j;
wherein the functions
a
k
l
depends on the distance
r
j
-
r
i
of the cell j to the cell i in the relation:
a
k
l
r
j
-
r
i
=
A
k
l
* exp(-
r
j
-
r
i
/
r
n
o
r
m
) with predefined constant coefficients
A
00
,
A
11
,
A
20
,
A
02
; and wherein the coefficients
A
00
,
A
11
,
A
20
,
A
02
, d and
r
n
o
r
m
are determined by optimizing the correlation of the response score with a therapy response of a cohort of training patients (claim 104).
The claims encompass unlimited number of ways (because the options for variables are unlimited) to generate single-cell ADC score and/or response score; unlimited ways to optimizing the correlation of the response score with a therapy response of a cohort training patients.
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
As set forth above, The amended claims would still encompass: 1) unlimited options of
d
(distance); 2) unlimited options for functions of
a
00
,
a
11
,
a
20
,
a
02
; 3) unlimited options for predefined constant coefficients
A
00
,
A
11
,
A
20
,
A
02
. In addition, because different ADCs would have different physical/chemical properties such as stability and/or permeability, different ADCs may have different therapeutic activities to the neighboring cells. Thus, the choices of distance (unlimited), functions (unlimited) and coefficients (unlimited) need to be tested and optimized for each cancer (unlimited), for each ADC (unlimited), and for each different cohort of training patients. The performance of each variable and/or function settings are not predictable and need to be tested and optimized. Given the calculation formula, the choice of one variable (e.g. distance) would impact the choice of other variables.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Fig. 34 of the instant specification describes “QCS Positive” if at least 90% of cell exhibit an optical density of HER2 membrane staining above an optical density cut-off of 0.0365; Figs. 35 and 36 shows that patients with more than 95% of cells had an optical density above a cut-off of 0.04077 or within a minimum distance (20 μm) of a positive cells have higher survival probability ([0187], [0188]); Fig. 38 uses HER2-positve cell density and a neighborhood score based on a distance of 25 μm ([0195]); Fig. 39 uses HER2-positve cell density and a neighborhood score based on a distance of 20 μm, the distance dependent weighting is calculated by
e
x
p
(
-
0.5
*
(
d
i
s
t
/
s
i
g
m
a
)
^
2
)
([0196]). Figs. 40 and 41 use HER2-positve cell density and a neighborhood score based on a distance of 20 μm ([0197], [0198]). All results are based on the same ADC: Trastuzumab deruxtecan. Taken together, the specification mainly describes methods of selecting patient population based on HER2-positive cell density and a neighborhood score based on the total number of cells within 20 μm or 25 μm of HER2-positive cells for the specific ADC.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent 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."
In order to expand the teaching of the application to use the claimed methods, a considerable amount of experimentation is needed given the unlimited variables encompassed by the claimed methods, including at least unlimited ADCs, unlimited cancers, unlimited distance choices, unlimited function selections to reach a response score, unlimited optimization methods.
Due to the large quantity of experimentation necessary to test the use of screening method; the lack of direction/guidance presented in the specification; the state of the prior art which establishes the unpredictability in the field; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention in its full scope.
Response to Arguments
For the Enablement rejection of claims 84, 86, 87, 91-101, 103-107, 111-121, and 123 under 35 U.S.C. 112(a), Applicant argues:
At the outset, Applicant notes that the ADC of the claims is not "unlimited," but rather is an ADC that comprises an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is human epidermal growth factor receptor 2 (HER2). Further, at paragraph [00171], the Specification as filed explains that using an embodiment of FIG. 26 for calculating single-cell ADC score as reflected in the claims, certain constants including rnorm and d (distance) can be "the same for all types of cancer." Thus, one of ordinary skill in the art would not necessarily need to test and optimize for the choice of distance and coefficients for each cancer and ADC, as asserted by the Office Action.
Regarding the assertion that the claims encompass an unlimited number of options ford (distance), functions a00, au, a20, and a02, and constant coefficients A00, A11, A20, and A02, the pending claims have been amended to clarify that the recited functions are exponential functions. Further, at paragraphs [0155] and [0156] the Specification describes how network weights, which include the coefficients (Akl) and distance, can be found using optimization algorithms. In particular, such weights can be determined by, e.g., generating manual annotation layers for nuclei and membranes in multiple training images and then adjusting by an optimization algorithm the weights so that the generated posterior layers are most similar to the manually generated annotation layers. See Specification as filed, paragraph [0155]. Such optimization is also reflected in the pending claims, which recite, in part, "optimizing the correlation of the response score with a therapy response of a cohort of training patients." Thus, one of ordinary skill in the art using a function as recited in the pending claims and appropriate corresponding training data would readily understand how to determine the coefficients and distance, such that they could select these parameters empirically to best predict which cancer patients would be responsive to the methods of treatment recited in the pending claims.
Applicant’s arguments have been considered but have not been found persuasive. The claimed method is based on the anti-HER2 ADC can have inhibiting activity to HER2-positive cancer tells and neighboring HER2-negative cancer cells, see paragraphs [000186]-[0188] of instant publication US 2024/0426826. The effects of an anti-HER2 ADC on neighboring cells would depend on: 1) the expression level of HER2 on HER2-positive cancer cells; 2) the distance between HER2-negative cancer cells and HER2-positive cells; 3) the stability and permeability of the ADC; and 4) the environmental condition of the cancer. For example, if an ADC has good stability and permeability and the HER2-positive cancer cells express high level of HER2, the ADC can have inhibiting activity for HER2-negative cells at a greater distance. Thus, the property of an ADC and a cancer would impact the choice of variables in calculating the ADC and treatment scores, also the correlation between the scores and the effectiveness of a treatment.
As set forth above, all results in the specification are based on only one ADC: Trastuzumab deruxtecan. The specification mainly describes methods of selecting patient population based on HER2-positive cell density and a neighborhood score based on the total number of cells within 20 μm or 25 μm of HER2-positive cells for the specific ADC. Based on the limited examples presented in the specification, one of ordinary skilled in the art would not be able to how to optimizing the correlation of the response score with a therapy response of a cohort of training patients, because as set forth in the rejection, there are unlimited ways to get a response score. It would require undue experimentation to find a suitable response score which has best correlation with a therapy response.
Thus, the rejection is maintained for reasons of record.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646
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